Preparation and use of aryl alkyl acid derivatives for the treatment of obesity

ABSTRACT

This invention relates to certain aryl alkyl acid compounds, compositions, and methods for treating or preventing obesity and related diseases.

[0001] This application claims benefit of U.S. Provisional ApplicationSer. No. 60/469,619, filed May 9, 2003, the contents of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to certain aryl alkyl acid compounds,compositions, and methods for treating or preventing obesity and relateddiseases.

BACKGROUND OF THE INVENTION

[0003] Obesity, which is an excess of body fat relative to lean bodymass, is a chronic disease that is highly prevalent in modern society.It is associated not only with a social stigma, but also with decreasedlife span and numerous medical problems, including adverse psychologicaldevelopment, coronary artery disease, hypertension, stroke, diabetes,hyperlipidemia, and some cancers. (see, e.g., Nishina, et al., Metab.43:554-558, 1994; Grundy and Barnett, Dis. Mon. 36:641-731, 1990;Rissanen, et al., British Medical Journal, 301:835-837, 1990).

[0004] Obesity remains a problem, and treatment has been limited. Thereis, therefore, a need to develop pharmaceuticals and treatment regimeseffective in the alleviation of obesity.

[0005] A hallmark characteristic of obesity is an increase in whiteadipose tissue (WAT) mass that is largely due to accumulation oftriacylglycerol. This increase in WAT mass is a key contributor toobesity-associated complications. Diacylglycerol O-acyltransferases(DGATs, EC 2.3.1.2) are membrane-bound enzymes that catalyze theterminal step of triacylglycerol biosynthesis. Two enzymes that displayDGAT activity have been characterized: DGAT-1 (diacylglycerolO-acyltransferase type 1) (see, e.g., U.S. Pat. No. 6,100,077; Cases, etal., Proc. Nat. Acad. Sci. 95:13018-13023, 1998) and DGAT-2(diacylglycerol O-acyltransferase type 2) (Cases, et al., J. Biol. Chem.276:38870-38876, 2001). DGAT-1 and DGAT-2 do not exhibit significantprotein sequence identity. Importantly, DGAT-1 null mice do not becomeobese when challenged with a high fat diet in contrast to wild-typelittermates (Smith, et al., Nature Genetics 25:87-90, 2000). DGAT-1 nullmice display reduced postprandial plasma glucose levels and exhibitincreased energy expenditure, but have normal levels of serumtriglycerides (Smith, et al., 2000), possibly due to the preservedDGAT-2 activity. Since DGAT-1 is expressed in the intestine and adiposetissue (Cases, et al., 1998), there are at least two possible mechanismsto explain the resistance of DGAT-1 null mice to diet-induced obesity.First, abolishing DGAT-1 activity in the intestine may block thereformation and export of triacylglycerol from intestinal cells into thecirculation via chylomicron particles. Second, knocking out DGAT-1activity in the adipocyte may decrease deposition of triacylglycerol inWAT. The phenotype of the DGAT-1 null mouse, along with the results ofour studies with DGAT-1 inhibitors in diet-induced obese (DIO) mice,indicate that a DGAT-1 inhibitor has utility for the treatment ofobesity and obesity-associated complications.

DETAILED DESCRIPTION OF THE INVENTION

[0006] The invention relates to aryl alkyl acid derivatives, andpharmaceutical salts and esters thereof, that have utility in theinhibition of DGAT-1 (diacylglycerol O-acyltransferase type 1) and inthe treatment of obesity and related diseases.

[0007] One embodiment of the invention is a compound of Formula (I)

[0008] wherein

[0009] Q is O, S, or NR⁵;

[0010] A is a linker selected from

[0011] wherein p is 1 or 2

[0012] and

[0013] wherein m is 0 and n is 1, 2, 3, or 4,

[0014] or

[0015] m is 1 and n is 1, 2,or 3,

[0016] and

[0017] wherein said linker is optionally substituted by one or two R⁸groups;

[0018] R¹ and R² are independently selected from hydrogen, halo,(C₁-C₆)alkyl, and (C₁-C₆)alkoxy;

[0019] R³ is selected from

[0020] hydrogen,

[0021] (C₁-C₆)alkyl optionally substituted by hydroxy,

[0022] and

[0023] phenyl optionally substituted with (C₁-C₆)alkyl, (C₁-C₆)alkoxy,or halo;

[0024] R⁴ is selected from hydrogen, nitro, and (C₁-C₆)alkyl;

[0025] or

[0026] R³ and R⁴ may, when taken together with the carbon atoms to whichthey are attached, form a benzene ring optionally substituted with up totwo substituents selected from

[0027] halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano,(C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, bis[(C₁-C₆)alkyl]aminocarbonyl,aminosulfonyl, (C₁-C₆)alkylaminosulfonyl,bis[(C₁-C₆)alkyl]aminosulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylsulfonylamino, hydroxy-(C₂-C₆)alkylaminocarbonyl,1-morpholinylcarbonyl, and 1-piperidinylcarbonyl,

[0028] and

[0029] when two of said benzene ring substituents are (C₁-C₆)alkyl andare attached to adjacent carbon atoms of the benzene ring, they may bejoined together to form a 5-7-membered carbocyclic ring;

[0030] R⁵ is hydrogen or (C₁-C₆)alkyl;

[0031] R⁶ is hydrogen;

[0032] R⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with

[0033] (C₁-C₆)alkoxy,

[0034] bis[(C₁-C₃)alkyl]amino

[0035] or

[0036] phenyl optionally substituted with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, or

[0037] cyano;

[0038] or

[0039] R⁶ and R⁷ are both (C₁-C₆)alkyl;

[0040] or

[0041] R⁶ and R⁷ may form, together with the carbon atom to which theyare attached,

[0042] a 3- to 5-membered carbocyclic ring,

[0043] or

[0044] a 6-membered ring represented by

[0045] wherein W is CH₂, C(CH₃)₂, O, NR⁹, S, or SO₂;

[0046] R⁸ is (C₁-C₆)alkyl;

[0047] and

[0048] R⁹ is hydrogen or (C₁-C₆)alkyl;

[0049] or the pharmaceutically acceptable salts and esters thereof.

[0050] A second embodiment of this invention is a compound of Formula(Ia)

[0051] wherein

[0052] Q, A, and R¹-R⁴ have the meanings as described above for Formula(I)

[0053] or the pharmaceutical salts and esters thereof.

[0054] A third embodiment of the invention is a compound of Formula (Ib)

[0055] wherein

[0056] Q, A, and R¹-R⁴ have the meanings as described above for Formula(I),

[0057] or pharmaceutical salts and esters thereof.

[0058] Examples of the invention may be found in the Examples describedbelow and in Tables 1 and 2. The compounds described in the Examples areintended to be representative of the invention, and it will beunderstood that the scope of the invention is not limited by the scopeof the examples. Those skilled in the art will recognize that theinvention may be practiced with variations on the disclosed structures,materials, compositions and methods, and such variations are regarded aswithin the ambit of the invention.

[0059] The terms identified above have the following meaning throughout:

[0060] The term “halo” means F, Br, Cl, and I.

[0061] The terms “(C₁-C₆)alkyl,” and “(C₂-C₆)alkyl” mean a linear orbranched saturated hydrocarbon groups having from about 1 to about 6carbon atoms, or from 2 to about 6 carbon atoms, respectively. Thehydrocarbon group may also include a cyclic alkyl radical as part of thealkyl group. Such groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, cyclopropyl,cyclohexyl, cyclopropyl-methyl, and cyclopentyl-methyl groups.

[0062] The term “(C₁-C₆)alkoxy” means a linear or branched saturatedhydrocarbon group having from about 1 to about 6 carbon atoms, saidgroup being attached to an oxygen atom. The oxygen atom is the atomthrough which the alkoxy substituent is attached to the rest of themolecule. The hydrocarbon group may also include a cyclic alkyl radicalas part of the alkyl group. Such groups include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-hexyloxy,3,3-dimethylpropoxy, cyclopropoxy, cyclopropylmethoxy, cyclopentyloxy,and the like.

[0063] The term “(C₁-C₆)haloalkoxy” means a (C₁-C₆)alkoxy groupsubstituted on carbon with a halogen atom. Such groups includetrifluoromethoxy, difluoromethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 3-fluoropropoxy, 2-chloroethoxy, 3-chloropropoxy,1-fluoro-2,2,-dichloroethoxy, and the like.

[0064] The term “(C₁-C₆)haloalkyl” means a (C₁-C₆)alkyl groupsubstituted on carbon with a halogen atom. Such groups includetrifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl,difluoroethyl, 1-fluoro-2,2-dichloroethyl, 3-chloropropyl, 4-bromohexyl,and the like.

[0065] The terms “aminocarbonyl,” “(C₁-C₆)alkylaminocarbonyl,” and“bis[(C₁-C₆)alkyl]aminocarbonyl,” mean a carbonyl [C(═O)] groupsubstituted by nitrogen atom in which the nitrogen atom isunsubstituted, substituted by a single (C₁-C₆)alkyl group, or by two(C₁-C₆)alkyl groups, respectively. The carbonyl group is the point ofattachment of the substituent to the rest of the molecule. Such groupsinclude carboxamido [NH₂C(═O)—], N-methylcarboxamido [CH₃NHC(═O)],N-methyl-N-propylcarboxamido [CH₃CH₂CH₂N(CH₃)C(═O)—] andN,N-diethylcarboxamido [(CH₃CH₂)₂NC(═O)—], and the like.

[0066] The term “hydroxy-(C₂-C₆)alkylaminocarbonyl” means a carbonyl[C(═O)] group substituted by nitrogen atom in which the nitrogen atom issubstituted by a single (C₂-C₆)alkyl group, and said alkyl is furthersubstituted by a hydroxy group. Such groups include2-hydroxyethylamido-, 3-hydroxypropylamido, 4-hydroxyhexylamido, and thelike.

[0067] The terms “aminosulfonyl,” “(C₁-C₆)alkylaminosulfonyl,” and“bis[(C₁-C₆)alkyl]aminosulfonyl” mean a S(═O)₂ group substituted bynitrogen atom in which the nitrogen atom is unsubstituted, substitutedby a single (C₁-C₆)alkyl group, or by two (C₁-C₆)alkyl groups,respectively. The S(═O)₂ group is the point of attachment of thesubstituent to the rest of the molecule. Such groups includeaminosulfonyl [NH₂S(═O)₂—], N-methylaminosulfonyl-[CH₃NHS(═O)₂],N-methyl-N-propylaminosulfonyl [CH₃CH₂CH₂N(CH₃)S(═O)₂—] andN,N,-diethylaminosulfonyl [(CH₃CH₂)₂NS(═O)₂—], and the like.

[0068] The term “(C₁-C₆)alkylcarbonylamino” means an amino group inwhich the nitrogen atom is substituted by a carbonyl group, and saidcarbonyl group is further substituted by a (C₁-C₆)alkyl group. Thenitrogen atom is the point of attachment of the substituent to the restof the molecule. Such groups include acetylamino [CH₃C(═O)NH—],propanoylamino [CH₃CH₂C(═O)NH—],and i-butanoylamino[(CH₃)₂CHC(═O)NH—]groups, and the like.

[0069] The term “(C₁-C₆)alkylsulfonylamino” means an amino group inwhich the nitrogen atom is substituted by a sulfonyl [S(═O)₂] group, andsaid sulfonyl group is further substituted by a (C₁-C₆)alkyl group. Thenitrogen atom is the point of attachment of the substituent to the restof the molecule. Such groups include methylsulfonylamino [CH₃S(═O)₂NH—],propylsulfonylamino [CH₃CH₂CH₂S(═O)₂NH—], and i-propylsulfonylamino[(CH₃)₂CHS(═O)₂NH—] groups, and the like.

[0070] The terms “1-morpholinylcarbonyl” and “1-piperidinylcarbonyl”mean

[0071] The term “optionally substituted” means that the moiety somodified may have from none to up to at least the highest number ofsubstituents indicated. Each substituent may replace any hydrogen atomon the moiety so modified as long as the replacement is chemicallypossible and chemically stable. When there are two or more substituentson any moiety, each substituent is chosen independently of any othersubstituent and can, accordingly, be the same or different.

[0072] When any moiety is described as being substituted, it can haveone or more of the indicated substituents that can be located at anyavailable position on the moiety. When there are two or moresubstituents on any moiety, each term shall be defined independently ofany other in each occurrence.

[0073] Representative salts of the compounds of Formula (I), Formula(Ia), and Formula (Ib) include the conventional non-toxic salts and thequaternary ammonium salts which are formed, for example, from inorganicor organic acids or bases by means well known in the art. For example,such acid addition salts include acetate, adipate, alginate, ascorbate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate.

[0074] Base salts include alkali metal salts such as potassium andsodium salts, alkaline earth metal salts such as calcium and magnesiumsalts, and ammonium salts with organic bases such as dicyclohexylaminesalts and N-methyl-D-glucamine. Additionally, basic nitrogen containinggroups may be quaternized with such agents as lower alkyl halides suchas methyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

[0075] The esters in the present invention are non-toxic,pharmaceutically acceptable ester derivatives of the compounds ofFormula (I), Formula (Ia), and Formula (Ib). This includes, for example,ester derivatives of hydroxy-containing compounds of Formula (I),Formula (Ia), and Formula (Ib) prepared with acetic, benzoic, mandelic,stearic, lactic, salicylic, hydroxynaphthoic, glucoheptonic, andgluconic acid. This also includes, for example, ester derivatives ofcarboxylic acid-containing compounds of Formula (I) and Formula (Ia)prepared with pharmaceutically acceptable alcohols. Pharmaceuticallyacceptable alcohols include, but are not limited to methanol, ethanol,isopropanol, butanol, 2-methylpropanol, 2-methoxyethanol,2-(dimethylamino)ethanol, 2-(diethylamino)ethanol,2-(1-piperidinyl)ethanol, 2-(1-morpholinyl)ethanol, hydroxyacetic acid,N,N-dimethylglycolamide, hydroxyacetone ,and the like. It will also beapparent to those skilled in the art that compounds of Formula (Ia) arehydroxy acids and therefore may form cyclic esters (i.e., lactones).These esters, including those represented by Formula (Ib), areencompassed within the scope of the invention. The compounds of Formula(I), Formula (Ia), and Formula (Ib) may be esterified by a variety ofconventional procedures well known by those skilled in the art. Oneskilled in the art would readily know how to successfully carry outthese as well as other methods of esterification.

[0076] Sensitive or reactive groups on the compounds of Formula (I),Formula (Ia), and Formula (Ib) may need to be protected during any ofthe above methods for forming esters, and protecting groups may be addedand removed by conventional methods well known in the art.

[0077] The compounds of this invention may, either by nature ofasymmetric centers or by restricted rotation, be present in the form ofisomers. Any isomer may be present in which the asymmetric center is inthe (R)-, (S)-, or (R,S) configuration.

[0078] It will also be appreciated that when two or more asymmetriccenters are present in the compounds of the invention, that severaldiastereomers and enantiomers of the exemplified structures will oftenbe possible, and that pure diastereomers and pure enantiomers representpreferred embodiments. It is intended that pure stereoisomers, purediastereomers, pure enantiomers, and mixtures thereof, are within thescope of the invention.

[0079] All isomers, whether separated, pure, partially pure, or inracemic mixture, of the compounds of this invention are encompassedwithin the scope of this invention. The purification of said isomers andthe separation of said isomeric mixtures may be accomplished by standardtechniques known in the art.

[0080] Geometric isomers by nature of substituents about a double bondor a ring may be present in cis (═Z-) or trans (═E-) form, and bothisomeric forms are encompassed within the scope of this invention.

[0081] The particular process to be utilized in the preparation of thecompounds of this invention depends upon the specific compound desired.Such factors as the selection of the specific moieties and the specificsubstituents on the various moieties, all play a role in the path to befollowed in the preparation of the specific compounds of this invention.These factors are readily recognized by one of ordinary skill in theart.

[0082] For synthesis of any particular compound, one skilled in the artwill recognize that the use of protecting groups may be required for thesynthesis of compounds containing certain substituents. A description ofsuitable protecting groups and appropriate methods of adding andremoving such groups may be found, for example, in Protective Groups inOrganic Synthesis, Second Edition, T. W. Greene, John Wiley and Sons,New York, 1991.

[0083] In the reaction schemes below, one skilled in the art willrecognize that reagents and solvents actually used may be selected fromseveral reagents and solvents well known in the art to be effectiveequivalents. When specific reagents or solvents are shown in a reactionscheme, therefore, they are meant to be illustrative examples ofconditions desirable for the execution of that particular reactionscheme. Abbreviations not identified in accompanying text are listedlater in this disclosure under “Abbreviations and Acronyms.”

[0084] Another object of this invention is to provide methods of makingthe compounds of the invention. The compounds may be prepared fromreadily available materials by the methods outlined in the reactionscheme and Examples below, and by obvious modifications thereto.

General Preparation of Compounds of the Invention

[0085] Preparation of the compounds of the present invention havingFormula (I), may be accomplished by either of the two general methodsshown below in Reaction Scheme 1 and Reaction Scheme 2.

[0086] In Reaction Scheme 1, a coupling reaction of the compound ofFormula (II) with nitrophenylboronic acid or boronic ester of Formula(III), in the presence of a palladium catalyst such as PdCl₂(dppf),gives the intermediate of Formula (V). Reduction of the nitro group inthe compound of Formula (V) can be accomplished by standard means suchas iron/acetic acid to provide the corresponding amino compound ofFormula (VI). An alternative route to the compounds of Formula (VI) isto carry out a palladium-catalyzed coupling reaction of the compound ofFormula (II) with the optionally protected anilino boronic acid/boronicester of Formula (IV), followed by deprotection, if necessary, toprovide the compound of Formula (VI) directly. The nitro or aminoboronic acid/boronic ester reagents (III and (IV), respectively, areeither commercially available or can be prepared from the correspondingreadily available halonitrobenzenes by means well known in the art.

[0087] The compound of Formula (VI) is then allowed to react with the2-halo-substituted heterocycle and related compounds of Formula (VI) togive the compounds of Formula (VIII) where R≠H or Formula (I) when R═H.The Formula (VIII) compounds can be hydrolyzed under standard esterhydrolysis conditions to give the compounds of Formula (I).

[0088] Alternatives for the preparation of compounds of Formula (VII),useful when boronic acids or boronic esters of Formulae (III) and (IV)are not readily accessible, are shown in Reaction Scheme 2 below.Preparation of the boronic ester of Formula (X) from the correspondingcompound of Formula (II) is accomplished by reaction of (II) with aboronic ester reagent such as pinnacol borane to afford the intermediateof Formula (X). This boronic acid/ester reagent of Formula (X) can becoupled with the 2-anilino-heterocycle of Formula (IX) in the presenceof a palladium catalyst and a base such as potassium carbonate, to givethe intermediate of Formula (VIII). The Formula (VIII) compound can alsobe prepared by carrying out a coupling reaction of (X) with theoptionally protected haloaniline of Formula (XI), providing anadditional route to the intermediate of Formula (VI). Hydrolysis of(VIII), as described in Reaction Scheme 1, provides the compound ofFormula (I).

[0089] Compounds of Formula (II) may be prepared from a readilyavailable anhydride of Formula (XI) or an acid chloride-ester of Formula(XII by a standard Friedel-Crafts acylation reaction as shown inReaction Scheme 3.

[0090] Intermediates of Formula (XIII) are either commercially availableor can be prepared in straightforward manner from readily availableprecursors. A general method of preparation of Formula (XIIIa) [(XIII)where A=—(CH₂)C(R⁶)(R⁷)—] is shown in Reaction Scheme 4. Esterificationof a substituted carboxylic acid of Formula (XV) gives a substitutedester of Formula (XVI); alkylation of the ester with t-butylbromoacetate gives the diester of Formula (XVII). Selective removal ofthe t-butyl group under acidic conditions provides the monoacidmonoester of Formula (XVIII) which can be converted by standard means(e.g., SOCl₂) to the ester-acid chloride of Formula (XIIIa).

[0091] Compounds of Formula (II) in which A is

[0092] R⁶ is H, and p is 1, can be prepared as shown in Reaction Scheme5, by alkylating a substituted malonic ester of Formula (XIX) with thephenacyl bromide of Formula (XX), in the presence of a strong base suchas sodium hydride, to give the intermediate of Formula (XXI). Hydrolysisand decarboxylation of (XXI) provides the compound of Formula (IIa) [(I)where A is —(CH₂)CH(R⁷)—].

[0093] The preparation of Formula (II) compounds in which A is

[0094] m is 0, and n is 1, 2, 3, or 4, and is optionally substituted byup to two R⁸ groups is summarized in Reaction Scheme 6. This ReactionScheme illustrates a general method of obtaining Formula (II) compoundswhere stereoisomers are possible, and specifically shows the preparationof (R,R) diastereomers of Formula (IId) and Formula (IIe).

[0095] In Reaction Scheme 6, the anhydride of Formula (XIIb) [Formula(XII) where A is

[0096] m is 0, n is 1, 2, 3, or 4, and is optionally substituted by upto two R⁸ groups] is converted in two steps to the compound of Formula(XIb) [Formula (XII) where A is defined as above for Formula (XII)]. Themethod of Reaction Scheme 3 is followed to prepare the compound ofFormula (IIb) from (XIIIb). Formula (IIb) may be converted to thecompound of Formula (IIc) by basic hydrolysis. If desired, (IIc) may beresolved into its optical antipodes by standard means, for example, viaselective crystallization of its diastereomeric salts with an opticallyactive base such as (R)- or (S)-1-phenylethylamine, and liberating theoptically purified compound by acidification of the salt. Thus, thecompound of Formula (IId) can be prepared and converted to thecorresponding ester of Formula (Ie).

[0097] It is to be understood that intermediates of Formulae (IIb) to(IIe) may be individually carried on to the corresponding Formula (I)compounds by the methods outlined in Reaction Schemes 1 and 2 above,thus allowing the preparation of different diastereomeric compounds ofFormula (I).

[0098] Formula (IIb)-(IIe) represent Formula (II) where A is

[0099] m is 0; n is 1, 2, 3, or 4; and A is optionally substituted by upto two R⁸ groups

[0100] Other compounds of Formula (II) can be prepared by methods knownin the art and by the methods described herein, for example, by usingcompounds 1 (prepared as described in McDonald, et al., J. Org. Chem.35:2666-2669, 1970), 2 (prepared as described in Hronowski, et al., Can.J. Chem.66:61-70, 1988), (3 prepared as described in Chung, et al.,Bioorg. Med. Chem. Lett. 5:1097-1102, 1995; Seetz, et al., Rec. Trav.Chim. Pays-Bas 107:160-162, 1988), 4 (prepared as described in Jun, etal., Bull. Korean Chem. Soc. 9:206-209, 1988); 5 (see, e.g., methodsdescribed in U.S. Pat. No. 6,562,828); 6 and 7 (see, e.g., methodsdescribed in Carlon, et al., Org. Prep. Proc. Int. 9:94-96, 1977; U.S.Pat. No. 3,256,277; Bushweller, et al., J. Org. Chem. 54:2404-2409,1989).

[0101] In addition, compounds of Formula (II) can be prepared byapplying other methods known in the art. For example, to prepare thefollowing specific compounds of Formula (II), designated 8-13, thefollowing methods may be employed: 8 (see, e.g., WO 9615096 and U.S.Pat. No. 5,789,434); 2 (see, e.g., methods described in WO 9717317); 10(see, e.g., methods described in van der Mey, et al., J. Med. Chem.44:2511-2522, 2001; Gaare, et al., Acta Chem. Scand. 51:1229-1233, 1997;Kuchar, et al., Coll. Czech. Chem. Commun. 51:2617-25, 1986); 11 (see,e.g., methods described in Kawamatsu, et al., Arzneim. Forsch.30:454-459, 1980; Bajaj, et al., J. Indian Chem. Soc. 52:1076-1078,1975); 12 and 13 (see, e.g., methods described in WO 9615096, and Sen,et al,. Indian J. Chem. 23B:821-824, 1984).

[0102] Compounds of Formula (IX) can be prepared by reaction of ananiline of Formula (XXII) by allowing reaction with a compound ofFormula (VII), generally by heating together in an inert solvent. Thismethod is illustrated in Reaction Scheme 7.

[0103] Other compounds of Formula (IX) can be prepared by other methodsknown in the art, for example, by the reaction of a 2-oxoethylthiocyanate with an aniline of Formula (XXII) to form a2-(arylamino)-thiazole as described in the art (Sharma, et al.,Tetrahedron, 15:53-59, 1961; Schantl, et al., Synth.Commun.28:1451-1462, 1998).

[0104] Compounds of Formula (VII) can be prepared by methods known inthe art, such as the following: (a) 2-chloro-5-cyanobenzothiazole and2-chloro-6-cyanobenzothiazole (WO 2002000633); (b)5-acetamido-2-chlorobenzothiazole (Sharpe, et al., J. Med. Chem.15:523-529, 1972); (c) 6-acetamido-2-chlorobenzothiazole (Katz, J. Am.Chem. Soc. 73:4007-4010, 1951); (d) 2-chloro-5-benzothiazolecarboxamide,2-chloro-N-methyl-6-benzothiazolecarboxamide,2-chloro-N-ethyl-5-benzothiazolecarboxamide,2-chloro-N,N-dimethyl-5-benzothiazolecarboxamide,2-chloro-N,N-dimethyl-6-benzothiazolecarboxamide,2-chloro-N-(2-hydroxyethyl)-5-benzothiazolecarboxamide,2-chloro-N-(2-hydroxyethyl)-6-benzothiazolecarboxamide, and2-chloro-7-morpholinocarbonyl-benzothiazole (U.S. Pat. No. 3,654,296);(e) 6-butoxy-2-chloro-benzothiazole (Bordi, et al., Farmaco 49:153-166,1994); (f) 2-chloro-6-isopropoxy-benzothiazole,2-chloro-5-cyano-benzoxazole, and 5-cyano-2-methylthiobenzothiazole(Eur. Patent Appl. EP1308439A1); (g)2-chloro-5-methylsulfonyl-benzoxazole (Lok, et al., J. Org. Chem.61:3289-3297, 1996); (h) 2-chloro-5-(4-methyl-phenyl)-thiazole,2-chloro-5-(4-isopropyl-phenyl)-thiazole, and2-chloro-5-(2,4-dimethyl-phenyl)-thiazole (Merijanian, et al., J. Org.Chem. 51:543-545, 1986; (i) 2-chloro-5-(4-methoxy-phenyl)-thiazole (Fr.Demande FR 2152345); (j) 2-chloro-4,5-dimethylthiazole (Begtrup, et al.,Acta Chem. Scand. 46:372-383, 1992); (k)2-chloro-4-hydroxymethylthiazole (WO 2000078746); (l)2-chloro-4-methylthiazole (Eur. Pat. Appl. EP1216997); (m)2-chloro-5-cyanobenzoxazole, 2-chloro-benzimidazole-5-carbonitrile,2-chloro-5-trifluoromethylbenzimidazole, 2-chloro-5-fluorobenzimidazole,2,5-dichlorobenzimidazole, 2-chloro-5-nitrobenzimidazole,2-chloro-1-methylbenzimidazole,2-chloro-5-trifluoromethyl-1-methylbenzimidazole, and2-chloro-5-fluoro-1-methylbenzimidazole (Eur. Pat. Appl. EP1308439A1);(n) 2-chloro-1-methyl-benzimidazole, 2-chloro-1-ethyl-benzimidazole,2-chloro-1-isopropyl-benzimidazole, 2-chloro-1-benzyl-benzimidazole, and2-chloro-6-fluoro-1-methyl-1-benzimidazole (WO 2001047898); (o)2-chloro-1-cyclopropyl-benzimidazole (Orjales, et al., J. Med. Chem.40:586-593, 1997); (p) 2-chloro-7-methoxy-1-isopropyl-benzimidazole and2-chloro-5-fluoro-1-isopropyl-benzimidazole (Fr. Demande FR 2773800).

[0105] The compounds having Formula (Ia) can be prepared from compoundsof Formula (I) or Formula (VI), by the use of selective reducing agentsand methods for selective reduction known to those skilled in the art.For example, a compound of Formula (I) can be treated with sodiumborohydride or similar reducing agent to afford the correspondingcompound of Formula (Ia).

[0106] Formula (Ib) compounds are prepared from Formula (Ia) compoundsby standard methods for lactonization of hydroxy acids (e.g. in thepresence of an acid catalyst such as TsOH) in an anhydrous solvent suchas toluene.

[0107] Examples of the invention may be found in the Examples describedbelow and in Tables 1 and 2. The compounds described in the Examples areintended to be representative of the invention, and it will beunderstood that the scope of the invention is not limited by the scopeof the examples. Those skilled in the art will recognize that theinvention may be practiced with variations on the disclosed structures,materials, compositions and methods, and such variations are regarded aswithin the ambit of the invention.

PREPARATION OF COMPOUNDS OF THE INVENTION General Information

[0108] Mass Spectra

[0109] Chemical ionization mass spectra (CI-MS) were obtained with aHewlett Packard 5989A mass spectrometer equipped with a Hewlett Packard5890 Gas Chromatograph with a J & W DB-5 column (0.25 uM coating; 30m×0.25 mm). The ion source was maintained at 250° C. and spectra werescanned from 50-800 amu at 2 sec per scan.

[0110] Liquid chromatography—electrospray mass spectra (LC-MS) data wereobtained by using one of the following two methods. In the Examples andTables provided below, the LC-MS data are given with HPLC retentiontimes (ret. time). Except as noted otherwise, Method 1 was used.

[0111] Method 1: Hewlett-Packard 1100 HPLC equipped with a quaternarypump, a variable wavelength detector set at 254 nm, a YMC pro C-18column (2×23 mm, 120A), and a Finnigan LCQ ion trap mass spectrometerwith electrospray ionization. Spectra were scanned from 120-1200 amuusing a variable ion time according to the number of ions in the source.The eluants were A: 2% acetonitrile in water with 0.02% TFA, and B: 2%water in acetonitrile with 0.018% TFA. Gradient elution from 10% B to95% B over 3.5 minutes at a flow rate of 1.0 mL/min was used with aninitial hold of 0.5 minutes and a final hold of 0.5 minutes at 95% B.Total run time was 6.5 minutes.

[0112] Method 2: Gilson HPLC system equipped with two Gilson 306 pumps,a Gilson 215 Autosampler, a Gilson diode array detector, a YMC Pro C-18column (2×23 mm, 120 A), and a Micromass LCZ single quadrupole massspectrometer with z-spray electrospray ionization. Spectra were scannedfrom 120-800 amu over 1.5 seconds. ELSD (Evaporative Light ScatteringDetector) data was also acquired as an analog channel. The eluants wereA: 2% acetonitrile in water with 0.02% TFA, and B: 2% water inacetonitrile with 0.018% TFA. Gradient elution from 10% B to 90% B over3.5 minutes at a flow rate of 1.5 mL/min was used with an initial holdof 0.5 minutes and a final hold of 0.5 minutes at 90% B. Total run timewas 4.8 minutes. An extra switching valve was used for column switchingand regeneration.

[0113] NMR Spectra

[0114] Routine one-dimensional NMR spectroscopy was performed on 300 MHzor 400 MHz Varian Mercury-plus spectrometers. The samples were dissolvedin deuterated solvents obtained from Cambridge Isotope Labs, andtransferred to 5 mm ID Wilmad NMR tubes. The spectra were acquired at293° K. The chemical shifts were recorded on the ppm scale and werereferenced to the appropriate solvent signals, such as 2.49 ppm forDMSO-d₆, 1.93 ppm for CD₃CN, 3.30 ppm for CD₃OD, 5.32 ppm for CD₂Cl₂,and 7.26 ppm for CDCl₃ for ¹H spectra; and 39.5 ppm for DMSO-d₆, 1.3 ppmfor CD₃CN, 49.0 ppm for CD₃OD, 53.8 ppm for CD₂Cl₂ and 77.0 ppm forCDCl₃ for ¹³C spectra.

[0115] Chiral Chromatography

[0116] Chiral chromatography was carried out by using Pirkle Covalent(R,R) Whelk-O 2 10/100 from Regis Technologies as the stationary phase.The mobile phase consisted of A=Hexane (containing 0.1% TFA) andB=isopropyl alcohol (containing 0.1% TFA). The usual gradient was 10% Bto 60% B over 25 minutes. In some cases, a gradient of 10 to 90% B or 50to 90% B was used. Quantification and fraction collection was based onUV detection at 330 nm (also at 280 nm). Samples were typicallydissolved in DMF prior to injection; for analytical work, these samplesolutions were diluted further with methanol. For analytical work, a4.6×250 mm column, flow rate=1 mL/min, and Shimadzu analytical HPLC wereused. For preparative work, a 20×250 mm column, flow rate=25 mL/min, andGilson HPLC were used, with a typical injected sample quantity of 50 mg.

[0117] Abbreviations and Acronyms

[0118] When the following abbreviations are used throughout thedisclosure, they have the following meaning: aq aqueous BuOH butanolCDCl₃ deuterated chloroform Celite ® diatomaceous earth filter agent,® Celite Corp. DCE dichloroethane DCM dichloromethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d₆ deuterateddimethyl sulfoxide- ee enantiomeric excess EI-MS electron impact - massspectrometry ESI-MS electrospray ionization - mass spectrometry EtOHethanol EtOAc ethyl acetate h hour(s) iPrOH isopropanol GC-MS gaschromatography - mass spectrometry HPLC high pressure liquidchromatography HRMS high resolution mass spectrometry LC-MS liquidchromatography - mass spectrometry MeI methyl iodide MeOH methanol minminutes MS mass spectroscopy NMR nuclear magnetic resonance PdCl₂(dppf)1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) p.o. orallyadministered Rf TLC retention factor rt room temperature TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

Preparation of Compounds of Formula (II), (V) and (VI) Intermediate AMethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0119]

[0120] 4-Iodoformanilide

[0121] Step 1. To a solution of 4-iodoaniline (30.0 g, 137 mmol) in 100mL THF and 100 mL toluene, a solution of acetic anhydride (16.0 g, 157mmol) and formic acid (10.8 g, 235 mmol) was slowly added from anaddition funnel under argon atmosphere. The reaction mixture temperaturewas maintained below 15° C. during the addition. After the addition wasfinished, the reaction mixture was stirred at rt overnight. The reactionmixture was diluted with water (300 mL) and ethyl acetate (200 mL). Theorganic layer was separated, washed with water (2×200 mL), and 200 mLsaturated aqueous sodium bicarbonate solution. After drying over sodiumsulfate, the mixture was concentrated under reduced pressure to afford4-Iodoformanilide as an off-white solid (33.5 g, >98%). ¹H NMR (DMSO-d₆)δ 10.27 (s, 1H), 8.26 (d, J=2 Hz, 1H), 7.64 (d, J=12 Hz, 2H), 7.40 (d,J=11.7 Hz, 2H) and 30% tautomer; ESI-MS m/z 248.0 (MH⁺).

[0122] 4-(4-Bromophenyl)-2.2-dimethyl-4-oxobutanoic acid

[0123] Step 2. To a chilled solution (ice/water bath) of bromobenzene(7.71 g, 49.1 mmol) and 3,3-dimethyldihydro-2,5-furandione (5.99 g, 46.7mmol) in dichloroethane (150 mL) was added aluminum trichworide (13.28g, 99.58 mmol). The ice bath was removed and the reaction mixture wasstirred at rt overnight. The mixture was again chilled in an ice/waterbath, and then quenched with 1 M aqueous hydrochloric acid. Water (70mL) was added and the layers were separated. The aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by flash chromatography (Biotageapparatus, 17:83 ethyl acetate/hexane) to give4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid as a white solid (8.34g, 63%). LC-MS: ret. time 2.79 min; m/z 284.8 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 1.36 (s, 6H), 3.27 (s, 2H), 7.60 (d, 2H), 7.81 (d, 2H).

[0124] Methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate

[0125] Step 3. To a solution of4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid (8.33 g, 29.2 mmol)and 2,2-dimethoxypropane (3.95 g, 37.9 mmol) in methanol (100 mL) wasadded 1 M HCl in dioxane (2.0 mL). The reaction mixture was stirred at50° C. for 22 h. The mixture was concentrated under reduced pressure.Toluene (2×60 mL) was added and the mixture concentrated again (2×) toafford methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate as anoff-white, semi-solid (8.60 g, 99%). This material was used in the nextstep without further purification. LC-MS: ret. time 3.23 min; m/z 298.8(MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 1.34 (s, 6H), 3.28 (s, 2H), 3.67(s,3H), 7.58 (d, 2H), 7.78 (d, 2H).

[0126] Methyl4-[4′-(formylamino)-1.1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate

[0127] Step 4. To a 2-L three-necked round-bottomed flask were charged4-iodoformanilide (30.0 g, 121 mmol, 1.0 eq), bis(pinacolato)diboron(30.8 g, 121 mmol, 1.0 eq), palladium acetate (0.82 g, 3.6 mmol, 3 mol%), potassium acetate (35.70 g, 364.3 mmol), and 500 mLN,N-dimethylformamide. The mixture was degassed by gently bubbling argonthrough the solution for 30 minutes at rt. The mixture was then heatedat 80° C. under argon until the reaction was complete (2-3 hours). Afterthe mixture was cooled to rt, methyl4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (36.3 g, 121 mmol), cesiumcarbonate (59.4 g, 182 mmol), and palladium tetrakistriphenylphosphine(4.2 g, 3.6 mmol, 3 mol%) were added. The reaction mixture was thenheated at 80° C. overnight under argon. The mixture was cooled to rt,and slowly diluted with water (1.5 L), which caused solid material toprecipitate. The solids were removed by filtration, and washed with 500mL water. Then the solids were dissolved in 500 mL methylene chloride,and black particles were removed by passing the solution through a padof Celite®. The filtrate was washed with 150 mL water (2×). After thesolution was dried over sodium sulfate, the solution was concentratedunder reduced pressure to afford a dark, brown residue. The residue wasstirred in ethyl acetate (200 mL) and hexane (200 mL) for 1 h. Afterfiltration and drying, methyl4-[4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate wasobtained as a yellow solid (28.0 g, 68%). ¹H NMR (CDCl₃) δ 8.42 (d, J=2Hz, 1H), 7.98 (d, J=8 Hz, 2H), 7.62 (m, 6H), 3.70 (s, 3H), 3.33 (s, 2H),1.35 (s, 6H) and 40% tautomer; ESI-MS m/z 340.1 (MH⁺).

[0128] Methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0129] Step 5. To a suspension of methyl4-[4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate(2.40 g, 7.07 mmol) in 20 mL methanol, was added 7 mL concentratedhydrochloric acid at below rt. The reaction mixture was stirred at rtovernight. The mixture was concentrated under reduced pressure andsaturated aqueous sodium bicarbonate solution was slowly added untilpH>8.0. The aqueous layer was then extracted with methylene chloride(2×25 mL), and the combined organic layer was dried over sodium sulfate.The mixture was concentrated under reduced pressure to afford methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate as a lightred solid (2.1 g, 95%). ¹H NMR (CDCl₃) δ 7.96 (d, J=9 Hz, 2H), 7.60 (d,J=9 Hz, 2H), 7.46 (d, J=9 Hz, 2H), 6.76 (d, J=9 Hz, 2H), 3.85 (br s,2H), 3.69 (s, 3H), 3.32 (s, 2H), 1.35 (s, 6H); ESI-MS m/z 312.4 (MH⁺);HRMS m/z calcd for MH⁺312.1594, found 312.1597.

Intermediate B Ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenyl-ethyl)butanoate

[0130]

[0131] Diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)-malonate

[0132] Step 1. To a 500 mL 3-neck round-bottom flask equipped with anargon inlet and an addition funnel, was added sodium hydride (95%, 1.40g, 58.3 mmol) followed by tetrahydrofuran (30 mL). The resultingsuspension was then cooled to 0° C. and diethyl2-(2-phenylethyl)malonate (14.0 g, 53.0 mmol) in tetrahydrofuran (20 mL)was added dropwise over 20 minutes. The cooling bath was removed and thereaction mixture was allowed to warm to rt over 45 minutes. A solutionof 2-bromo-1-(4-bromophenyl)ethanone (14.72 g, 58.26 mmol) intetrahydrofuran (40 mL) was rapidly added and the resulting orange-redmixture was stirred at rt for 16 h. The mixture was carefully pouredinto 300 mL of 1N hydrochloric acid, and the resulting mixture wasstirred for 10 minutes and extracted twice with ethyl acetate. Thecombined extracts were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane)to afford diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (14.8 g,61%). LC-MS ret. time 3.89 min, m/z 461.2 (MH⁺); ¹H NMR (300 MHz, CDCl₃)δ 1.26 (t, 6H), 2.41-2.45 (m, 2H), 2.56-2.59 (m, 2H), 3.67 (s, 2H), 4.23(q, 4H), 7.14-7.22 (m, 3H), 7.22 (d, 2H), 7.61 (d, 2H), 7.79 (d, 2H).

[0133] Ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate

[0134] Step 2. To a solution of diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-phenylethyl)malonate (7.89 g, 17.1mmol) in acetone (18.5 mL) and ethanol (17.0 mL) was added 1 N aqueoussodium hydroxide solution (17.1 mL), and the resulting solution washeated at 50° C. for 3 h. Solvent was then removed under reducedpressure via rotary evaporation and the resulting residue was furtherconcentrated under high vacuum for 1 h. The residue was redissolved indimethoxyethane (18.5 mL) and the solution was heated at 80° C. for 2.5h. The mixture was cooled to rt, diluted with ethyl acetate, and washedwith water. The organic layer was dried over anhydrous sodium sulfateand concentrated under high vacuum. The resulting residue was purifiedby flash chromatography (Biotage flash 75, 10:90 ethyl acetate/hexane)to afford ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate (4.32g, 65%). LC-MS ret. time 3.79 min, m/z 389.2 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 1.20 (t, 3H), 1.78-1.94 (m, 2H), 2.62 (t, 2H), 2.86-3.01 (m,2H), 3.26-3.36 (m, 1H), 4.10 (q, 2H), 7.05-7.11 (m, 3H), 7.18-7.23 (m,2H), 7.51 (d, 2H), 7.72 (d, 2H).

[0135] Ethyl4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethylbutanoate

[0136] Step 3. Ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate(4.32 g, 11.1 mmol) and 4-nitrophenylboronic acid (2.22, 13.3 mmol) wasadded to a dry flask under argon. Toluene (100 mL), dioxane (25 mL),saturated aqueous sodium carbonate (30 mL), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II) (1:1 complex withdichloromethane, 453 mg, 0.55 mmol) were added and the mixture wasthoroughly degassed. The resulting mixture was then heated at 85° C. for16 h before it was cooled to rt. Water was added and the mixture wasextracted twice with ethyl acetate. The combined extracts were driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by flash chromatography (Biotage flash 75, 5:1ethyl acetate/hexane) to afford ethyl4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.6 g,75%). HPLC ret. time 3.99 min, ¹H NMR (300 MHz, CDCl₃) δ 1.29 (t, 3H),1.85-2.08 (m, 2H), 2.71 (t, 2H), 3.05-3.20 (m, 2H), 3.45-3.52 (m, 1H),4.20 (q, 2H), 7.18-7.31 (m, 5H), 7.72 (d, 2H), 7.78 (d, 2H), 8.05 (d,2H), 8.33 (d, 2H).

[0137] Ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenyl-ethyl)butanoate

[0138] Step 4. To a solution of ethyl4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (5.35g, 12.4 mmol) in 85% ethanol (160 mL) was added iron powder (6.94 g)followed by a 2 N aqueous solution of hydrochloric acid (6.2 mL). Theresulting mixture was refluxed for 2.5 h, filtered through a pad ofCelite®, and extracted with ethyl acetate. The combined organic extractswere dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (4.74g, 95%). LC-MS ret. time 3.22 min, m/z 402.0 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 1.18 (t, 3H), 1.83-2.10 (m, 2H), 2.65 (t, 2H), 3.03-3.12 (m,2H), 3.41-3.48 (m, 1H), 4.12 (q, 2H), 6.70 (d, 2H), 7.19 (d, 4H), 7.25(m, 1H), 7.38 (d, 2H), 7.53 (d, 2), 7.89 (d, 2H).

[0139] This intermediate compound ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-2-phenylethyl)-butanoate, aracemic mixture, was separated into its two (R) and (S) enantiomericisomers by preparative chiral HPLC using a Pirkle Covalent (R,R) Whelk-O2 10/100 column (25 cm×21.1 mm), and a solvent elution gradient of 50%isopropanol in hexane to 85% isopropanol in hexane, containing 0.1%trifluoroacetic acid, at a flow rate of 30 mL/min. Monitoring byultraviolet detection (254 nm) enabled the identification and isolationof enantio-enriched samples of the two isomers, which could be used toprepare individual (R) and (S) enantiomers of compounds of theinvention.

Intermediate C Ethyl2-[2-(4′-amino-1,1′-biphenyl-4yl)-2-oxoethyl]pentanoate

[0140]

[0141] Diethyl 2-[2-(4-bromophenyl)-2-oxoethyl]-2-propylmalonate

[0142] Step 1. To a 100 mL 3-neck flask was added sodium hydride (95%,0.55 g, 22 mmol) followed by tetrahydrofuran (13 mL). The suspension wascooled to 0° C., and a solution of diethyl propylmalonate (4.00 g, 19.8mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. Thecooling bath was removed and the reaction mixture was allowed to warm tort over 45 minutes. A solution of 2,4′-bromoacetophenone (5.50 g, 19.8mmol) in tetrahydrofuran (30 mL) was added via addition funnel over 10minutes, and the resulting orange-red reaction mixture stirred at rt for16 h. The reaction mixture was slowly poured into 1.0 N aqueoushydrochloric acid solution (100 mL) cooled to 0° C. stirred for 15minutes, followed by addition of ethyl acetate (100 mL) and water (100mL), and the layers separated. The aqueous layer was extracted withadditional ethyl acetate (75 mL), the combined organic layers werewashed with saturated aqueous sodium chloride solution (75 mL), driedover anhydrous sodium sulfate, filtered in vacuo through 2.5 cmCelite®/2.5 cm silica, and the filtrate was concentrated under reducedpressure, to afford diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-propylmalonate (7.62 g, 86%). LC-MSret. time 3.74 min, m/z 399.0 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 0.82-0.98(m, 3H), 1.10-1.45 (m, 8H), 2.01-2.12 (m, 2H), 3.60 (s, 2H),4.10-4.30(m, 4H), 7.60 (d, 2H), 7.85 (d, 2H).

[0143] Ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate

[0144] Step 2. To a 200 mL flask was added crude2-[2-(4-bromophenyl)-2-oxoethyl]-2-propylmalonate (7.62 g, 19.2 mmol),acetone (21 mL), and ethanol (19 mL), followed by addition of 1 Naqueous sodium hydroxide solution (19.1 mL). The reaction mixture washeated to 55° C. for 3 h. The clear, orange-red reaction mixture wasthen concentrated under reduced pressure and the residue was redissolvedin dimethoxyethane (30 mL). The mixture was heated to 80° C. for 3 h.The reaction mixture was cooled to rt, diluted with ethyl acetate (100mL) and water (100 mL), and stirred for 15 minutes until almost allcolor was extracted into the organic layer. The layers were separatedand the aqueous layer extracted with additional ethyl acetate (75 mL).The combined organic layers were washed with saturated aqueous sodiumchloride solution (75 mL), dried over anhydrous sodium sulfate, andconcentrated under reduced pressure to afford an orange oil. The crudeproduct was purified by flash chromatography (10:1 hexane:ethyl acetate)to afford ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g,20%). LC-MS ret. time 3.60 min, m/z 326.05 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 0.87 (t, 3H), 1.25 (t, 3H), 1.29-1.43 (m, 2H), 1.57-1.73 (m,2H), 2.90-3.08 (m, 2H), 3.34-3.47 (m, 2H), 4.15 (q, 2H), 7.59 (d, 4H),7.82 (d, 2H).

[0145] Ethyl 2-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate

[0146] Step 3. To a 150 mL 3-neck flask fitted with a reflux condenserwas added ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g, 4.10mmol) and 4-nitro phenyl boronic acid (0.81 g, 4.9 mmol), dissolved intoluene (37 mL) and dioxane (10 mL), followed by addition of saturatedaqueous sodium carbonate (11 mL). A thin-gauge needle was inserted intothe bi-phasic mixture and the mixture was degassed with argon over 30minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.17 g, 0.20 mmol) was added, followed by 15minutes of degassing. The mixture was heated to 85° C. for 16 h. Thevery darkly colored reaction mixture was allowed to cool, and dilutedwith ethyl acetate (100 mL) and saturated aqueous sodium chloridesolution (100 mL). The layers were separated, the aqueous layerextracted twice with ethyl acetate (50 mL), and the combined organiclayers were washed with saturated aqueous sodium chloride solution (75mL), dried over anhydrous magnesium sulfate, and filtered in vacuothrough 2 cm Celite®/2 cm silica. The filtrate was concentrated underreduced pressure, leaving a dark red-brown oil, that was purified byflash chromatography (10:1 hexane:ethyl acetate, then 7:1 hexane:ethylacetate, then 4:1 hexane:ethyl acetate) to afford ethyl2-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate (0.71 g, 48%).LC-MS ret. time 3.88 min, m/z 369.8 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ0.95 (t, 3H), 1.30 (t, 3H), 1.35-1.50 (m, 2H), 1.60-1.83 (m, 2H),3.0-3.18 (m, 2H), 3.5 (dd, 1H), 4.20 (q, 2H), 7.65-7.88 (overlappingd,4H), 8.10 (d, 2H), 8.35 (d, 2H).

[0147] Ethyl 2-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate

[0148] Step 4. To a 100 mL flask fitted with a reflux condenser wasadded ethyl 2-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate(0.71 g, 1.9 mmol) dissolved in 85% aqueous ethanol (24 mL), followed byaddition of 2 N aqueous hydrochloric acid solution (0.95 mL) and finelypowdered iron (0) (1.10 g, 19.1 mmol), and the reaction mixture heatedto 85° C. over 2 h. Upon cooling, the darkly colored reaction mixturewas filtered in vacuo through 2 cm Celite®/2 cm silica, resulting in alliron particulates/baseline material being removed. The yellow filtratewas concentrated under reduced pressure, resulting in a solid that wastriturated in 20 mL diethyl ether/20 mL hexane, affording methyl2-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]pentanoate as a tan solid(0.56 g, 88%). LC-MS ret. time 2.82 min, m/z 340.4 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 0.87 (t, 3H), 1.13 (t,3H), 1.25-1.40 (m, 2H), 1.44-1.64(m, 2H), 2.78-2.90 (m, 1H), 3.06-3.40 (m, 2H), 3.95-4.10 (m, 2H),5.30-5.64 (br s, 1H), 6.65 (d, 2H), 7.46 (d, 2H), 7.67 (d, 2H), 7.93 (d,2H).

Intermediate D Ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoate

[0149]

[0150] Diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-methoxyethyl)malonate

[0151] Step 1. In a 100 mL flask was added sodium hydride (95%, 0.25 g,10.1 mmol) followed by tetrahydrofuran (5 mL). The suspension was cooledto 0° C., and a solution of diethyl (2-methoxyethyl)-malonate (2.0 g,9.16 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10minutes. The cooling bath was removed, and the reaction mixture wasallowed to warm to rt over 45 minutes. A solution of2,4′-bromoacetophenone (2.55 g, 19.6 mmol) in tetrahydrofuran (15 mL)was added via addition funnel over 10 minutes, and the resultingorange-red reaction mixture was stirred at rt for 16 h. The reactionmixture was slowly poured into 1 N aqueous hydrochloric acid solution(50 mL) with cooling at 0° C., and stirred for 15 minutes. Ethyl acetate(75 mL) and water (75 mL) were added, and the layers were separated. Theaqueous layer was extracted with additional ethyl acetate (50 mL), andthe combined organic layers were washed with saturated aqueous sodiumchloride solution (75 mL), dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated in vacuo to yield 3.7 g of ayellow oil. This oil was purified by flash chromatography (10:1hexane/ethyl acetate, then 4:1 hexane/ethyl acetate) to afford diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-methoxyethyl)malonate (1.59 g,42%). LC-MS ret. time 3.40 min, m/z 415 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ1.20 (t, 6H), 2.38 (t, 2H), 3.09 (s, 3H), 3.40 (t, 2H), 3.74 (s, 2H),4.19 (q, 4H), 7.60 (d, 2H), 7.83 (d, 2H).

[0152] Ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate

[0153] Step 2. To a 150 mL flask was added diethyl2-[2-(4-bromophenyl)-2-oxoethyl]-2-(2-methoxyethyl)malonate (1.59 g,3.59 mmol) dissolved in acetone (16 mL) and ethanol (16 mL), followed byaddition of 1N aqueous sodium hydroxide solution (3.6 mL). The reactionmixture was then heated at 55° C. for 3 h. The reaction mixture wasconcentrated in vacuo to remove solvents, the residue redissolved indimethoxyethane (32 mL), and the reaction mixture heated at 80° C. for 3h. The reaction mixture was cooled to rt, diluted with ethyl acetate (50mL) and water (50 mL), and stirred for 15 minutes until almost all colorwas extracted into the organic layer. The layers were separated, theaqueous layer was extracted with additional ethyl acetate (50 mL), andthe combined organic layers were washed with saturated aqueous sodiumchloride solution (50 mL), dried over anhydrous sodium sulfate, andconcentrated in vacuo, to afford ethyl4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 86%). Nofurther purification of this material was required. LC-MS ret. time 3.18min, m/z 342.8 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ 1.35 (t, 3H), 1.77-1.92(m, 1H), 1.94-2.10 (m, 1H), 3.05-3.2 (m, 2H), 3.35-3.50 (m, 3H),4.09-4.25 (m, 2H), 7.60 (d, 2H), 7.83 (d, 2H).

[0154] Ethyl2-(2-methoxyethyl-4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxobutanoate

[0155] Step 3. To a 150 mL 3-neck flask fitted with a reflux condenserwas added ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate(1.06 g, 3.09 mmol) and 4-nitro-phenyl boronic acid (0.62 g, 3.70 mmol)dissolved in toluene (30 mL) and dioxane (8.50 mL), followed by additionof saturated aqueous sodium carbonate solution (8.50 mL). A thin-gaugeneedle was inserted into the bi-phasic mixture and degassed with argonover 30 minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.13 g, 0.15 mmol) was added, followed by anadditional 15 minutes of degassing. The reaction mixture was heated at85° C. for 16 h, and then the resulting dark-colored reaction mixturewas allowed to cool, and was diluted with ethyl acetate (75 mL) andsaturated aqueous sodium chloride solution (75 mL). The layers wereseparated, the aqueous layer was extracted twice with ethyl acetate (50mL), and the combined organic layers were washed with saturated aqueoussodium chloride solution (75 mL), dried over anhydrous magnesiumsulfate, and filtered in vacuo through 2 cm Celite®/2 cm silica. Thefiltrate was concentrated in vacuo, leaving a dark red-brown oil, thatwas purified by flash chromatography (4:1 hexane/ethyl acetate, then 3:1hexane/ethyl acetate, then 2:1 hexane/ethyl acetate) to afford ethyl2-(2-methoxyethyl)-4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxobutanoate (1.04g , 88%). LC-MS ret. time 3.38 min, m/z 385.9 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 1.27 (t, 3H), 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H), 3.10-3.25(m, 2H), 3.40-3.58 (m, 3H), 4.17 (q, 2H), 7.67-7.82 (2d, 4H), 8.10 (d,2H), 8.33 (d, 2H).

[0156] Ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoate

[0157] Step 4. To a 100 mL flask fitted with a reflux condenser wasadded ethyl2-(2-methoxyethyl)-4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxobutanoate (1.04g, 2.71 mmol) dissolved in 85% aqueous ethanol (24 mL), followed byaddition of 2 N aqueous hydrochloric acid solution (1.35 mL) and finelypowdered iron (0) (1.51 g, 27.1 mmol), and the reaction mixture washeated at 85° C. for 2 h. Upon cooling, the darkly-colored reactionmixture was filtered in vacuo through 2 cm Celite®/2 cm silica,resulting in all iron particulates and polar material being removed. Theyellow filtrate was concentrated in vacuo, resulting in a solid that waspurified by flash chromatography (3:1 hexane/ethyl acetate) affordingethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoateas a tan solid (0.89 g, 93%). LC-MS ret. time 2.33 min, m/z 356.2 (MH⁺);¹H NMR (300 MHz, CDCl₃) δ 1.18-1.33 (m, 3H), 1.79-2.10 (overlapping m,2H), 3.10-3.21 (m, 2H), 3.30 (s, 3H), 3.48 (t, 3H), 4.16 (t, 3H), 7.15(d, 2H), 7.55 (d, 2H), 7.62 (d, 2H), 8.03 (d, 2H).

Intermediate E

[0158] Methyl1-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate

[0159] Methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentanecarboxylate

[0160] Step 1. To a 150 mL flask was added dichloromethane (70 mL),methyl 1-(2-chloro-2-oxoethyl)cyclopentanecarboxylate ] (3.50 g, 16.8mmol) [prepared as described by Bajaj, et al., J. Indian Chem. Soc.52:1076-78, 1975] and bromobenzene (2.77 g, 17.6 mmol), and the reactionmixture cooled to 0° C. before aluminum trichloride (4.77 g, 35.7 mmol)was slowly added. The mixture was stirred for 1 h at 0° C. then for 12 hat rt. The reaction mixture was slowly poured into 50 mL chilled (0° C.)1 N aqueous hydrochloric acid solution. Water (50 mL) was added,followed by ethyl acetate (100 mL), and the mixture stirred for 30minutes. The layers were separated and the aqueous layer extracted withadditional ethyl acetate (100 mL). The combined organic layer was washedwith saturated aqueous sodium chloride (100 mL), dried over anhydroussodium sulfate, and concentrated under reduced pressure to yield a brownoil which was purified by flash chromatography (10:1/hexane:ethylacetate) to afford methyl 1-[2-(4-bromophenyl)-2-oxoethyl] cyclopentanecarboxylate as a yellow, crystalline solid (1.62 g, 30%). LC-MS ret.time 3.45 min, m/z 324.8 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 1.50-1.83(overlapping signals, 6H), 2.22-2.33 (m, 2H), 3.37 (s, 2H), 3.66 (s,3H), 7.59 (d, 2H), 7.80 (d, 2H).

[0161] Methyl1-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate

[0162] Step 2. To a 150 mL 3-neck flask fitted with a reflux condenserwas added methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentanecarboxylate(1.58 g, 4.64 mmol), 4-nitro phenyl boronic acid (0.93 g, 5.6 mmol),toluene (45 mL), and dioxane (13 mL), followed by the addition of asaturated aqueous sodium carbonate solution (13 mL). The mixture wasdegassed using argon and 1,2-bis[(diphenylphosphino) ferrocene]dichloropalladium(II) (0.19 g, 0.23 mmol) was added, followed by anadditional 15 minutes of degassing, and the deep red reaction mixturewas heated to 85° C. for 16 h. The very darkly colored reaction mixturewas allowed to cool, and then was diluted with ethyl acetate (100 mL)and saturated aqueous sodium chloride solution (100 mL). The layers wereseparated and the aqueous layer was extracted twice with ethyl acetate(50 mL). The combined organic layer was washed with saturated aqueoussodium chloride solution (100 mL), dried over anhydrous magnesiumsulfate, and filtered under reduced pressure through 2 cm Celite®/2 cmsilica. The filtrate was concentrated under reduced pressure, leaving adark red-brown oil, that was purified by flash chromatography(4:1/hexane: ethyl acetate, then 3:1/hexane: ethyl acetate, then2:1/hexane: ethyl acetate) to afford methyl1-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate(1.65 g, 93%). LC-MS ret. time 3.56 min, m/z 368.0 (MH⁺); ¹HNMR(300 MHz,CDCl₃) δ 1.56-1.85 (overlapping signals, 6H), 2.23-2.37 (m, 2H), 3.45(s, 2H), 3.67 (s, 3H), 7.70 (d, 2H), 7.77 (d, 2H), 8.06 (d, 2H), 8.34(d, 2H).

[0163] Methyl1-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate

[0164] Step 3. To a 100 mL flask fitted with a reflux condenser wasadded methyl1-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate(1.68 g, 4.40 mmol) dissolved in 85% aqueous ethanol (55 mL), followedby addition of 2 N aqueous hydrochloric acid solution (2.20 mL) andfinely powdered iron (0) (2.46 g, 44.1 mmol). The reaction mixture washeated to 85° C. over 2 h. Upon cooling, the darkly-colored reactionmixture was filtered under reduced pressure through 2 cm Celite®/2 cmsilica, in order to remove iron particulates and polar impurities. Theyellow filtrate was concentrated under reduced pressure, resulting in asolid that was triturated with 20 mL diethyl ether/20 mL hexane toafford methyl 1-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate as a light tan solid (1.20 g, 76%). LC-MS ret.time 2.71 min, m/z 338.1 (MH⁺); ¹HNMR (300 MHz, CDCl₃) δ 1.55-1.84(overlapping signals, 6H), 2.25-2.35 (m, 2H), 3.44 (s, 2H), 3.67 (s,3H), 7.40-8.10 (overlapping signals, 8H).

Intermediate F Methyl4-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate

[0165]

[0166] Methyl tetrahydro-2H-pyran-4-carboxylate

[0167] Step 1. Tetrahydro-2H-pyran-4-carboxylic acid (1.00 g, 7.68 mmol)was slowly added to a stirred suspension of anhydrous potassiumcarbonate (1.17 g, 8.45 mmol) in acetone (40 mL), followed by dimethylsulfate (0.8 mL, 8.45 mmol). The mixture was stirred and heated for 3 h.The inorganic salts were then removed by filtration and washed withacetone, and the filtrate was dried and concentrated to give methyltetrahydro-2H-pyran-4-carboxylate (1.1 g, 99%), which was used in thenext step without further purification. GC-MS m/z 145 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 11.70-1.80 (m, 4H), 2.47-2.52 (m, 1H), 3.34-3.43 (m, 2H),3.65 (s, 3H), 3.88-3.95 (m, 2H).

[0168] Methyl4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate

[0169] Step 2. Diisopropylamine (1.28 mL, 9.16 mmol) was diluted withtetrahydrofuran (2 mL) and cooled to −78° C. n-Butyllithium (2.5 M, 3.66mL, 9.16 mmol) was added dropwise, and the solution was allowed to stirfor 1 h. Methyl tetrahydro-2H-pyran-4-carboxylate (1.1 g, 7.63 mmol) wasadded as a solution in tetrahydrofuran (1.5 mL) at −78° C. The mixturewas allowed to warm to −35° C. and stirred for 1 h. tert-Butylbromoacetate (1.58 mL, 10.7 mmol) was added neat at −35° C. The mixturewas allowed to warm to 0° C. and stirred for 2 h. The mixture wasstirred at rt overnight. Water was added at 0° C. and the mixtureextracted with ethyl acetate. The organic phase was washed with brine,and dried over sodium sulfate. The crude product was purified by flashchromatography (Biotage Flash 40M, 6:1 hexane/ethyl acetate) to affordmethyl 4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate(1.12 g, 56%). LC-MS ret. time 2.47 min, m/z 258.7 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 1.38 (s, 9H), 1.52-1.61 (m, 2H), 2.00-2.07 (m, 2H), 2.50(s, 2H), 3.52-3.60 (m, 2H), 3.70 (s, 3H), 3.71-3.77 (m, 2H).

[0170] [4-(Methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid

[0171] Step 3. To a solution of methyl4-(2-tert-butoxy-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.1 g,4.26 mmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid(5.0 mL) and the resulting solution was stirred at rt for 5 h. Themixture was concentrated under reduced pressure to afford[4-(methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (900 mg, 94%),which was used in the next step without further purification. LC-MS ret.time 0.93 min, m/z 202.9 (MH⁺); ¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.70(m, 2H), 2.10-2.15 (m, 2H), 2.68 (s, 2H), 3.62-3.71 (m, 2H), 3.72 (s,3), 3.79-3.86 (m, 2H).

[0172] Methyl 4-(2-chloro-2-oxoethyl-1tetrahydro-2H-pyran-4-carboxylate

[0173] Step 4. Thionyl chloride (20 mL) was added to[4-methoxycarbonyl)tetrahydro-2H-pyran-4-yl]acetic acid (970 mg, 4.80mmol) and the solution was stirred at rt for 3 h. The solvent was thenremoved and mixture was azeotroped with dichloroethane three times toafford methyl 4-(2-chloro-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate(1.05 g, 99%), which was used without purification in the next step.

[0174] Methyl4-[2-(4-bromophenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate

[0175] Step 5. To a solution of methyl4-(2-chloro-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.06 g, 4.8mmol) and bromobenzene (1.13 g, 7.21 mmol) in dichloromethane (20 mL) at0° C. was added aluminum chloride (1.92 g, 14.4 mmol). The ice-waterbath was removed and the reaction mixture was stirred at rt for 16 h.The mixture was then cooled at 0° C. and quenched by the addition of 1 NHCl solution and water. The mixture was extracted with dichloromethane,and the combined organic phases were dried over sodium sulfate. Thecrude material was then purified by flash chromatography (Biotage Flash40 M, 2:1 hexane/ethyl acetate, to afford methyl4-[2-(4-bromo-phenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (900mg, 55%). LC-MS ret. time 2.76 min; m/z 342.9 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 1.58-1.69 (m, 2H), 2.12-2.18 (m, 2H), 3.28 (s, 2H), 3.64 (s,3H), 3.69-3.77 (m, 4H), 7.59 (d, 2H), 7.77 (d, 2H).

[0176] Methyl4-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate

[0177] Step 6. Methyl4-[2-(4-bromophenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (820mg, 2.40 mmol) and 4-nitrophenyl boronic acid (481 mg, 2.88 mmol) werecombined in a dry flask under argon. Toluene (20 mL) and dioxane (5 mL)were added, and the resulting solution was degassed for 30 minutes by aflow of argon. The degassing was continued during the addition ofsaturated aqueous sodium carbonate (6 mL) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1complex with dichloromethane (98 mg, 0.12 mmol). The resulting mixturewas then heated at 85° C. for 16 h before it was cooled to rt. Water wasadded, and the aqueous layer was extracted twice with ethyl acetate. Thecombined organic phases were then dried over anhydrous sodium sulfateand concentrated under reduced pressure. The resulting residue waspurified by flash chromatography (Biotage Flash 40) using 1:1 ethylacetate/hexane to afford methyl4-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate(730 mg, 79%). LC-MS ret. time 3.03; m/z 383.9 (MH⁺);¹H NMR (300 MHz,CDCl₃) δ 1.65-1.73 (m, 2H), 2.17-2.21 (m, 2H), 3.37 (s, 2H), 3.68 (s,3H), 3.71-3.78 (m, 4H), 7.70 (d, 2H), 7.77 (d, 2H), 8.02 (d, 2H), 8.31(d, 2H).

[0178] Methyl4-[2-(4′-amino-1,1′-biphenyl-4-4-yl-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate

[0179] Step 7. To a solution of methyl4-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate(1.24 g, 3.25 mmol) in 85% ethanol (50 mL) was added iron powder (1.81g), followed by 2 N aqueous HCl (1.62 mL), and the resulting mixture wasrefluxed for 2.5 h. The mixture was then filtered through a pad ofCelite® and the filtrate was extracted with dichloromethane. Thecombined organic phases were then dried over anhydrous sodium sulfateand concentrated in vacuo to afford methyl4-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate(1.05 g, 91%). LC-MS ret. time 2.20; m/z 354.0 (MH⁺); ¹H NMR (300 MHz,CDCl₃) δ 1.57-1.66 (m, 2H), 2.09 (m, 2H), 3.28 (s, 2H), 3.61 (s, 3H),3.64-3.71 (m, 4H), 6.76 (d, 2H), 7.42 (d, 2H), 7.54 (d, 2H), 7.88 (d,2H).

Intermediate G Methylcis-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate

[0180]

[0181] Methyl cis-2-(4-bromobenzoyl)cyclohexanecarboxylate

[0182] Step 1. To a solution ofcis-2-(4-bromobenzoyl)-1-cyclohexanecarboxylic acid (4.0 g, 12.85 mmol)in MeOH (50 mL) was added 2,2-dimethoxypropane (2.01 g, 19.28 mmol) andHCl (4.0 M in dioxane, 1.20 mL). The resulting solution was stirred at40° C. for 3 days, and then evaporated to dryness. The resulting residuewas purified by flash chromatography (Biotage Flash 40M) using 3 to 6%ethyl acetate in hexanes to afford methylcis-2-(4-bromobenzoyl)cyclohexane-carboxylate (1.76 g, 42%). LC-MS ret.time 3.40; m/z 326 (MH⁺); ¹H NMR (400 MHz, CD₂Cl₂) δ 1.35-1.51 (m, 3H),1.72-1.86 (m, 2H), 1.91-2.05 (m, 2H), 2.11-2.20 (m, 1H), 2.74 (m, 1H),3.58 (s, 3H), 3.82 (q, 1H), 7.62 (m, 2H), 7.73 (m, 2H).

[0183] Methylcis-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate

[0184] Step 2. Methyl cis-2-(4-bromobenzoyl)cyclohexanecarboxylate (1.76g, 5.41 mmol) and 4-amino phenyl boronic acid (1.13 g, 6.49 mmol) wereadded to a clean dry flask under argon. Toluene (50 mL), EtOH (20 mL),and 3 M aqueous Na₂CO₃ (14 mL, 43 mmol) were added, and resultingsolution was degassed for 30 minutes by using a flow of argon. Then[1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1complex with dichloromethane (442 mg, 0.54 mmol) was added and theresulting mixture was heated at 85° C. for 16 h. The mixture was cooledto rt, and then diluted with EtOAc and passed through a Celite® pad. Thesolvent was removed by rotary evaporation. Water and EtOAc were added,and the aqueous layer was extracted with EtOAc. The combined organicphases were washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (Biotage Flash 40M) using 33 to 40% ethyl acetatein hexane to afford methylcis-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate.(1.54g, 84%). LC-MS ret. time 3.99; m/z 338 (MH⁺); ¹H NMR (400 MHz, CD₂Cl₂) δ1.37-1.53 (m, 3H), 1.74-1.88 (m, 2H), 1.90-1.99 (m, 1H), 2.04-2.22 (m,2H), 2.75 (m, 1H), 3.59 (s, 3H), 3.90 (q, 1H), 6.79 (m, 2H), 7.48 (m,2H), 7.63 (m, 2H), 7.89 (m, 2H).

Intermediate H trans-(Trimethylsilyl)ethyl2-(4-bromobenzoyl)cyclohexanecarboxylate

[0185]

[0186] To a solution of trans-2-(4-bromobenzoyl)cyclohexanecarboxylicacid (5.0 g, 16.07 mmol) in DCM (80 mL) was added2-(trimethylsilyl)ethanol (2.1 g, 17.68 mmol),N,N′-dimethylamino-pyridine (98 mg, 0.80 mmol), and EDCI (4.0 g, 20.89mmol). The resulting reaction mixture was stirred at rt for 2 days.Water was added, and the mixture was diluted with DCM. The aqueous layerwas separated and extracted with DCM. The combined organic phases werewashed with water and brine, dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. Silica gelchromatography (Biotage cartridge), eluting with 10% EtOAc in hexanegave trans-(trimethylsilyl)ethyl2-(4-bromobenzoyl)cyclohexanecarboxylate (2.44 g, 37%). ¹H NMR (400 MHz,CD₂Cl₂) δ −0.01 (s, 9H), 0.85 (m, 2H), 1.45 (m, 3H), 1.73 (m, 2H), 1.90(m, 2H), 2.18 (m, 1H), 2.71 (m, 1H), 3.80 (m, 1H), 4.05 (m, 2H), 7.58(d, 2H), 7.70 (d, 2H).

Intermediate I Methyl trans-2-(4bromobenzoyl)cyclopropanecarboxylate

[0187]

[0188] cis-2-(4-Bromobenzoyl)cyclopropanecarboxylic acid

[0189] Step 1. To a cold (0° C.) stirred solution of bromobenzene (9.09g, 57.89 mmol) and AlCl₃ (18.36 g, 137.84 mmol) in dry DCM (150 mL) wasadded 3-oxabicyclo[3.1.0]hexane-2,4-dione (5.40 g, 48.24 mmol). Thereaction mixture was stirred at rt for 3 days. The dark-red solution wasthen poured into ice-cold water (120 mL), and conc. HCl (10 mL) wasadded. The solution was stirred for few minutes, and the layers wereseparated. The aqueous layer was extracted with DCM and the combinedorganic phases were washed with water, brine, dried over Na₂SO₄ andconcentrated to give cis-2-(4-bromobenzoyl)cyclopropanecarboxylic acid(9.69 g, 65%). LC-MS ret. time 2.50; m/z 270 (MH⁺);¹H NMR (400 MHz,CD₂Cl₂) δ 1.54 (m, 1H), 1.85 (m, 1H), 2.37 (m, 1H), 2.88 (m, 1H), 7.65(m, 2H), 7.90 (m, 2H).

[0190] Methyl cis-2-(4-bromobenzoyl)cyclopropanecarboxylate

[0191] Step 2. To a solution ofcis-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (10.6 g, 36.63 mmol)in MeOH (250 mL) was added 2,2-dimethoxypropane (9.54 g, 91.59 mmol) andHCl (4.0 M in dioxane, 3.50 mL). The resulting solution was stirred at40° C. for 3 days, and then evaporated to dryness. The resulting residuewas purified by flash chromatography (Biotage Flash 40M) using 15 to 25%ethyl acetate in hexanes to afford methylcis-2-(4-bromobenzoyl)-cyclopropanecarboxylate (10.34 g, 99%). ¹H NMR(400 MHz, CD₂Cl₂) δ 1.39 (m, 1H), 1.82 (m, 1H), 2.34 (m, 1H), 2.77 (m,1H), 3.54 (s, 3H), 7.65 (m, 2H), 7.89 (m, 2H).

[0192] trans-2-(4-Bromobenzoyl)cyclopropanecarboxylic acid.

[0193] Step 3. Methyl cis-2-(4-bromobenzoyl)cyclopropanecarboxylate(10.34 g, 36.52 mmol) was dissolved in MeOH (100 mL), and then 15 mL 50%aqueous NaOH solution was added. The reaction mixture was stirred at 40°C. for 3 days. Solvent was removed by rotary evaporation and the residuewas dissolved in water. Concentrated HCl was added to adjust the acidityto pH 1. The precipitate that formed was collected by filtration anddried in a vacuum oven overnight to givetrans-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.43 g, 95%). LC-MSret. time 2.51, m/z 270 (MH⁺); ¹H NMR (400 MHz, CD₂Cl₂) δ 1.68 (m, 2H),2.38 (m, 1H), 3.22 (m, 1H), 7.67 (m, 2H), 7.90 (m, 2H).

[0194] Methyl trans-2-(4-bromobenzoyl)cyclopropanecarboxylate.

[0195] Step 4. To a solution oftrans-2-(4-bromobenzoyl)cyclopropanecarboxylic acid (9.43 g, 32.59 mmol)in MeOH (200 mL) was added 2,2-dimethoxypropane (10.18 g, 97.77 mmol)and HCl (4.0 M in dioxane, 4.0 mL). The resulting solution was stirredat 40° C. overnight, and then evaporated to dryness. The resultingresidue was purified by flash chromatography (Biotage Flash 40M) using15 to 25% ethyl acetate in hexanes to afford methyltrans-2-(4-bromobenzoyl)cyclopropanecarboxylate (7.7 g, 83%). ¹H NMR(400 MHz, CD₂Cl₂) δ 1.68 (m, 2H), 2.37 (m, 1H), 3.21 (m, 1H), 3.65 (s,3H), 7.68 (m, 2H), 7.90 (m, 2H).

Intermediate J Methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopropanecarboxylate

[0196]

[0197] Methyl trans-2-(4-bromobenzoyl)cyclopropanecarboxylate (1.33 g,4.70 mmol) and 4-amino-phenyl boronic acid (0.98 g, 5.64 mmol) werecombined in a dry flask under argon. Toluene (25 mL), EtOH (10 mL), and3 M aqueous Na₂CO₃ (7 mL, 20 mmol) were added, and the resultingsolution was degassed for 30 minutes by using a flow of argon. Then[1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1complex with dichloromethane (383 mg, 0.47 mmol) was added, and theresulting mixture was heated at 85° C. for 16 h. The mixture was cooledto rt, then diluted with EtOAc and passed through a Celite® pad. Thesolvent was removed by rotary evaporation. Water and EtOAc were added,and the aqueous layer was extracted with EtOAc. The combined organicphases were washed with water, brine, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography (Biotage Flash 40M) using 33 to 40% ethyl acetatein hexane to afford methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]-cyclopropanecarboxylate(0.92 g, 66%). ¹H NMR (400 MHz, CD₂Cl₂) δ 1.60 (m, 2H), 2.35 (m, 1H),3.22 (m, 1H), 3.73 (s, 3H), 6.80 (m, 2H), 7.51 (m, 2H), 7.68 (m, 2H),8.05 (m, 2H).

Intermediate K Methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutanecarboxylate

[0198]

[0199] trans-2-(4-Bromobenzoyl)cyclobutanecarboxylic acid

[0200] Step 1. To a cold (0° C.) stirred solution of bromobenzene (10.98g, 69.94 mmol) and AlCl₃ (19.41 g, 145.71 mmol) in dry DCM (150 mL) wasadded cyclobutane dicarboxylic anhydride (7.35 g, 58.28 mmol). Thereaction mixture was stirred at rt for 3 days. The dark-red solution wasthen poured into ice-cold water (120 mL), and conc. HCl (10 mL) wasadded. The solution was stirred for a few minutes, the aqueous layer wasextracted with DCM, and then the combined organic phases were extractedwith 1 N aqueous NaOH. The aqueous layer was stirred at rt overnight.The solution was acidified by addition of conc. HCl to pH 1.5, extractedwith EtOAc, and the combined organic phases were washed with water,brine, dried over Na₂SO₄ and concentrated to givetrans-2-(4-bromobenzoyl)cyclobutanecarboxylic acid (8.20 g, 49). ¹H NMR(400 MHz, CD₂Cl₂) δ 2.20-2.44 (m, 4H), 3.67 (m, 1H), 4.21 (m, 1H), 7.64(m, 2H), 7.80 (m, 2H).

[0201] Methyl trans-2-(4-bromobenzoyl)cyclobutanecarboxylate

[0202] Step 2. To a solution oftrans-2-(4-bromobenzoyl)cyclobutanecarboxylic acid (8.2 g, 28.94 mmol)in MeOH (250 mL) was added 2,2-dimethoxypropane (3.65 g, 35.02 mmol) andHCl (4.0 M in dioxane) (2.0 mL). The resulting solution was stirred atrt for 3 days, and then evaporated to dryness. The resulting residue waspurified with flash chromatography (Biotage Flash 40M) using 4 to 11%ethyl acetate in hexanes to afford methyltrans-2-(4-bromobenzoyl)cyclobutanecarboxylate (6.21 g, 78%). ¹H NMR(400 MHz, CD₂Cl₂) δ 2.14-2.39 (m, 4H), 3.62 (m, 1H), 3.68 (s, 3H), 4.24(m, 1H), 7.63 (m, 2H), 7.80 (m, 2H).

[0203] Methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutanecarboxylate

[0204] Step 3. Methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutanecarboxylate(1.25 g, 4.21 mmol) and 4-aminophenyl boronic acid (0.88 g, 5.05 mmol)were combined in a dry flask under argon. Toluene (25 mL), EtOH (10 mL),and 3 M aqueous Na₂CO₃ (5.0 mL, 15 mmol) were added, and the resultingsolution was degassed for 30 minutes by using a flow of argon. Then[1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(H), 1:1complex with dichloromethane (343 mg, 0.42 mmol), was added and theresulting mixture was heated at 85° C. for 16 h. The mixture was cooledto rt, diluted with EtOAc, and passed through a Celite® pad. The solventwas removed by rotary evaporation. Water and EtOAc were added, and theaqueous layer was extracted with EtOAc. The combined organic phases werewashed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was purified by flashchromatography (Biotage Flash 40M) using 29 to 37% ethyl acetate inhexane to afford methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)-carbonyl]cyclobutanecarboxylate(0.91 g, 70%). LC-MS ret. time 2.24; m/z 310.4 (MH⁺);¹H NMR (400 MHz,CD₂Cl₂) δ 2.13-2.36 (m, 4H), 3.60 (m, 1H), 3.64 (s, 1H), 4.24 (m, 1H),6.73 (m, 2H), 7.43 (m, 2H), 7.59 (m, 2H), 7.88 (m, 2H).

Intermediate L Methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate

[0205]

[0206] Methyl trans-2-(4-bromobenzoyl)cyclopentanecarboxylate

[0207] Step 1. To a solution oftrans-2-(4-bromobenzoyl)cyclopentanecarboxylic acid (2.0 g, 6.26 mmol)in MeOH (70 mL) was added 2,2-dimethoxypropane (1.63 g, 15.65 mmol) andHCl (4.0 M in dioxane) (1.0 mL). The resulting solution was stirred at40° C. overnight and then evaporated to dryness. The resulting residuewas purified by flash chromatography (Biotage Flash 40M) using 7 to 11%ethyl acetate in hexanes to afford methyltrans-2-(4-bromobenzoyl)cyclopentanecarboxylate (1.62 g, 83%). ¹H NMR(400 MHz, CD₂Cl₂) δ 1.70-1.95 (m, 4H), 2.08-2.21 (m, 2H), 3.40 (m, 1H),3.64 (s, 3H), 4.04 (m, 1H), 7.64 (m, 2H), 7.86 (m, 2H).

[0208] Methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate

[0209] Step 2. Methyl trans-2-(4-bromobenzoyl)cyclopentanecarboxylate(1.60 g, 5.14 mmol) and 4-aminophenyl boronic acid (1.07 g, 6.17 mmol)were combined in a dry flask under argon. Toluene (25 mL), EtOH (10 mL),and 3 M aqueous Na₂CO₃ (8.50 mL, 25 mmol) were added and resultingsolution was degassed for 30 minutes by using a flow of argon. Then[1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1complex with dichloromethane (419.9 mg, 0.51 mmol), was added and theresulting mixture was heated at 85° C. for 16 h. The mixture was cooledto it, diluted with EtOAc, and passed through a Celite® pad. The solventwas removed by rotary evaporation. Water and EtOAc were added and theaqueous layer was extracted with EtOAc. The combined organic phases werewashed with water, brine, dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was purified by flashchromatography (Biotage Flash 40M) using 29 to 33% ethyl acetate inhexane to afford methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate(1.12 g, 67%). ¹H NMR (400 MHz, CD₂Cl₂) δ 1.71-1.97 (m, 4H), 2.17 (m,2H), 3.44 (m, 1H), 3.65 (s, 3H), 4.12 (m, 1H), 6.84 (m, 2H), 7.51 (m,2H), 7.66 (m, 2H), 8.00 (m, 2H).

Intermediate M (R,R)-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acidmethyl ester

[0210]

[0211] (±)-Cyclopentane-1,2-dicarboxylic acid monomethyl ester

[0212] Step 1. The anhydride tetrahydro-cyclopenta[c]furan-1,3-dione(50.0 g, 356.8 mmol, prepared as described by Wilkening, et al., SynComm. 14(3):227, 1984) was dissolved in methanol (250 mL), and themixture was then heated at 50-55° C. under N₂ for 5 h. NMR analysisshowed no starting material remaining. Methanol was removed by rotaryevaporation, and the residue was dried in vacuo to afford the desiredproduct as a colorless oil (60.0 g, 98%). ¹H NMR (CDCl₃) δ 3.65 (s, 3H),3.08 (m, 2H), 2.04 (m, 4H), 1.90 (m, 1H), 1.65 (m, 1H).

[0213] (±)-cis-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acid methylester

[0214] Step 2. A solution of the monomethyl ester (92.0 g, 534.3 mmol),SOCl₂ (116.3 mL, 1.60 mol), and DMF (1 mL) in 850 mL CH₂Cl₂ was stirredat rt overnight under N₂. NMR analysis showed little starting materialremaining. The solvent was removed by rotary evaporation at <40° C., andthe residue was dried in vacuo for 1 h. This dried residue was dissolvedin bromobenzene (337.6 mL, 3.2 mol), and AlCl₃ (142.5 g, 1.07 mol) wasthen added portionwise at <5° C. The reaction mixture turned dark brown,and was stirred at <5° C. for 4 h under N₂. NMR analysis then showedlittle starting material remaining. The reaction mixture was then slowlypoured into 2 L ice-water, and then 1 L EtOAc was added. After themixture was stirred for 10 minutes, the aqueous (top) layer wasseparated, and extracted with 500 mL EtOAc. The combined organic layerswere washed with water (2×1 L) and saturated NaHCO₃ solution (200 mL),and dried over Na₂SO₄. Removal of solvent and drying in vacuo provided175.0 g (>95%) of the desired product. ¹H NMR (CDCl₃) δ 7.80 (d, 2H),7.60 (d, 2H), 4.07 (m, 1H), 3.53 (s, 3H), 3.07 (m, 1H), 2.20 (m, 1H),2.00 (m, 4H), 1.70 (m, 1H).

[0215] (±)-trans-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acid

[0216] Step 3. A solution of NaOH (128.2 g, 3.2 mol) in 700 mL water wasadded to a solution of cis-2-(4-bromo-benzoyl)-cyclopentanecarboxylicacid methyl ester (166.3 g, 534.3 mmol) in MeOH (700 mL). The reactionmixture was stirred at rt overnight. NMR analysis showed that littlestarting material remained. After ca. 1 L solvent was removed by rotaryevaporation, the mixture was diluted with 1 L water. Conc. HCl wasslowly added with stirring at <15° C., to adjust the acidity to pH <6. Aprecipitate formed, and stirring was continued for 1 h. The solidprecipitate was filtered, and rinsed with water. The dried filter cakewas dissolved in 1 L EtOAc, and dried over Na₂SO₄. Removal of solventand drying in vacuo afforded the desired product (131 g, 83%). ¹H NMR(CDCl₃) δ 7.83 (d, 2H), 7.60 (d, 2H), 4.05 (m, 1H), 3.50 (m, 1H), 2.20(m, 2H), 2.00 (m, 1H), 1.78 (m, 3H).

[0217] (R,R)-trans-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acid

[0218] Step 4. A mixture of(±)-trans-2-(4-bromo-benzoyl)-cyclopentanecarboxylic acid (114.3 g,384.7 mmol) and (R)-(+)-alpha-methyl-benzylamine (23.3 g, 192.3 mmol) inCH₃CN (1125 mL) was heated at 90-95° C. under N₂ to provide a solution.The hot solution was allowed to cool slowly with slow stirringovernight. The crystallized solid was filtered, and rinsed with CH₃CN(50 mL). Drying in vacuo to a constant weight afforded 64.5 g of whitesolid (56% ee, by chiral HPLC). This solid was then dissolved in amixture of solvents (258 mL EtOH and 516 mL water) with heating at90-95° C. under N₂. The hot solution was allowed to cool slowly withslow stirring overnight. The solid formed was filtered, and rinsed with60 mL of 1:2 EtOH/water. After drying in vacuo to a constant weight,this white solid was stirred with 1 N HCl (500 mL) and EtOAc (500 mL)for 10 minutes. The organic layer was separated, washed with water(2×200 mL), and dried over Na₂SO₄. Removal of solvent and drying invacuo provided an off-white solid (30.5 g, 26.7%, >99% ee based onchiral HPLC). Chiral HPLC method: ChiralPAK AD analytical column, 5:95iPrOH/hexanes (both containing 0.1% TFA), 1.0 mL/min flow rate,retention times were 21.08 min and 23.40 min for the (S,S) and (R,R)isomers, respectively. ¹H NMR (CDCl₃) spectra were identical to that forthe racemic (±)-trans-2-(4-bromo-benzoyl)-cyclopentanecarboxylic acid.

[0219] (R,R)-trans-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acidmethyl ester

[0220] Step 5. A suspension of(R,R)-trans-2-(4-bromo-benzoyl)-cyclopentanecarboxylic acid (30.5 g,102.6 mmol), MeI (9.6 mL, 154.0 mmol), and NaHCO₃ (25.9 g, 307.9 mmol)in 360 mL DMF was stirred at rt under argon overnight. NMR analysisshowed little starting material remaining. Water (1 L) was added to thereaction mixture, and then concentrated HCl was slowly added withstirring at <15° C. to adjust the acidity to pH <7, and a precipitatewas formed. After the mixture was stirred for 1 h, the solid wasfiltered and rinsed with water (200 mL). The solid was dried in vacuo toa constant weight, to afford the desired product as a light yellow solid(29.5 g, 92.5%, 94.5% ee based on chiral HPLC). HPLC method: ChiralPAKAD analytical column, 5:95 iPrOH/hexanes (both containing 0.1% TFA), 1.0mL/min flow rate, retention times were 10.64 min and 12.98 min for the(S,S) and (R,R) isomers, respectively. ¹H NMR (CDCl₃) δ 7.82 (d, 2H),7.60 (d, 2H), 4.05 (m, 1H), 3.65 (s, 3H), 3.42 (m, 1H), 2.18 (m, 2H),1.90 (m, 1H), 1.80 (m, 3H).

Intermediate N (R,R)-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acidtert-butyl ester

[0221]

[0222] (R,R)-trans-2-(4-Bromo-benzoyl)-cyclopentanecarboxylic acid (2.0g, 6.73 mmol) was dissolved in CH₂Cl₂ (40 mL) at rt, followed byaddition of a few drops of conc. sulfuric acid. Isobutylene (ca. 2.0 g)was then introduced by gentle bubbling while the reaction mixture wascooled in an ice-water bath. The reaction was then stirred at rt for 60h and quenched by adding 40 mL saturated aqueous Na₂CO₃ solution. Theorganic layer was separated, washed with water, and dried over anhydroussodium sulfate. Removal of solvent under reduced pressure afforded thedesired tert-butyl ester as a clear oil which solidified upon standing(1.9 g, 80% yield). ¹H NMR (DMSO-d₆) δ 7.90 (d, 2H), 7.88 (d, 2H), 4.00(q, 1H), 3.10 (q, 1H), 2.10 (m, 1H), 1.90 (m, 1H). 1.50-1.80 (m, 4H),1.30 (s, 9H).

Intermediate O Methyl(1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate

[0223]

[0224] 2-Fluoro-4-iodophenylformamide

[0225] Step 1. To a cooled solution (0° C.) of 4-iodo-2 fluoroaniline(3.05 g, 12.9 mmol) in tetrahydrofuran (15 mL) and toluene (15 mL), wasslowly added a mixture of acetic anhydride (1.39 mL, 14.7 mmol) andformic acid (0.83 mL, 22.0 mmol). The reaction mixture was stirred at rtovernight, then diluted with ethyl acetate (100 mL) and 1N aqueous HCl(100 mL). The layers were separated, and the organic layer was washedwith water and saturated sodium carbonate solution, and dried oversodium sulfate. The solvent was removed under reduced pressure to afford2-fluoro-4-iodophenylformamide as an off-white solid (3.32 g, 97%).GC-MS ret. time 2.27 min, m/z 265 (M⁺); ¹H NMR (300 MHz, CDCl₃) δ:7.37-7.51 (m, 3H), 8.13 (t, 1H), 8.46 (s, 1H).

[0226] Methyl (1R2R)-2-{[-3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylate

[0227] Step 2. To a suspension of 2-fluoro-4-iodophenylformamide (5.11g, 19.28 mmol) bis(pinacolato)diboron (4.89 g, 19.28 mmol), potassiumacetate (5.67 g, 57.84 mmol), and palladium acetate (129 mg, 0.58 mmol)in N,N-dimethylformamide (125 mL) was bubbled through argon for 30minutes. The reaction mixture was then heated at 80° C. for 3 h. Afterthe mixture was cooled to rt, methyl(R,R)-2-(4-bromobenzoyl)cyclopentanecarboxylate (2.2 g, 7.35 mmol, 97%ee), tetrakis(triphenylphosphine)palladium(0) (668 mg, 0.58 mmol), andcesium carbonate (9.43 g, 28.92 mmol) were added, and the reactionmixture was then heated at 80° C. for 16 h. The mixture was then cooledto rt, quenched with water, extracted with ethyl acetate, and dried overanhydrous sodium sulfate. Solvent was then removed under reducedpressure and the crude product was purified by flash chromatography(Biotage 75) using 1:1 ethylacetate/hexane to afford methyl2-{[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentanecarboxylate(4.6 g, 65%). LC-MS ret. time 3.15 min, m/z 342.0 (MH⁺); ¹H NMR (300MHz, DMSO-d₆) δ 1.52-1.94 (m, 1H), 1.92-2.07 (m, 1H), 2.10-2.21 (m, 1H),3.48 (m, 1H), 3.55 (s, 3H), 4.12 (q, 1H), 7.59 (dd, 1H), 7.62 (dd, 1H),7.87 (d, 2H), 8.09 (d, 2H), 8.25 (t, 1H), 8.34 (s, 1H), 10.62 (s, 1H).

[0228] Methyl(1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate

[0229] Step 3. To a solution of methyl2-{[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-carbonyl}cyclopentanecarboxylate(4.24 g, 11.48 mmol) in methanol (34 mL) was added conc. HCl (11.4 mL),and the resulting solution was stirred at rt for 2 h. Solvent was thenremoved, the residual mixture was dissolved in water, and the acidity ofthe mixture was adjusted to pH ˜7 by slow addition of saturated aqueoussodium bicarbonate solution. The mixture was then extracted withdichloromethane and washed with saturated sodium chloride solution,dried over sodium sulfate, and the solvent was removed in vacuo. Thecrude mixture was then triturated with ethyl acetate/hexane to affordmethyl2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate(3.5 g, 89%, 80% ee). LC-MS ret. time 3.00 min, m/z 370.0 (MH⁺); ¹H NMR(300 MHz, DMSO-d₆) δ 5 1.52-1.84 (m, 4H), 1.97-2.02 (m, 1H), 2.14-2.18(m, 1H), 3.24-3.33 (m, 1H), 3.56 (s, 3H), 4.08 (q, 1H), 5.47 (br s, 2H),6.84 (t, 1H), 7.34 (dd, 1H), 7.48 (dd, 1H), 7.78 (d, 2H), 7.99 (d, 2H).

Intermediate P Methyl4-(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)-2.2-dimethyl-4-oxobutanoate

[0230]

[0231] Methyl4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate

[0232] Step 1. A suspension of 2-fluoro-4-iodophenylformamide (1.94 g,7.35 mmol, prepared as described above), bis(pinacolato)diboron (1.86 g,7.35 mmol), potassium acetate (2.16 g, 22.1 mmol), and palladium acetate(49.4 mg, 0.22 mmol) in N,N-dimethylformamide (50 mL) was degassed bybubbling a flow of argon through the mixture for 30 minutes. The mixturewas then heated at 80° C. for 3 h. After the mixture was cooled to rt,methyl 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (2.2 g, 7.4 mmol),tetrakis(triphenylphosphine)palladium(0) (254.8 mg, 0.22 mmol), andcesium carbonate (3.59 g, 11.0 mmol) were added, and the reactionmixture was heated at 80° C. for 16 h. The mixture was then cooled to rtand water was added. The mixture was extracted with ethyl acetate andthe combined extracts were dried over sodium sulfate. The mixture wasconcentrated under reduced pressure and the crude was purified by flashchromatography (Biotage Flash 40M, 1:1 ethyl acetate/hexane) to affordmethyl4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate(1.2 g, 46%). LC-MS ret. time 2.80 min, m/z 358.1 (MH⁺); ¹H NMR (300MHz, DMSO-d₆) δ 1.19 (s, 6H), 3.36 (s, 2H), 3.51 (s, 3H), 7.56 (d, 1H),7.69 (dd, 1H), 7.82 (d, 2H), 7.99 (d, 3H), 8.21 (t), 10.25 (s, 1H).

[0233] Methyl4-(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0234] Step 2. To a solution of methyl4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate(1.21 g, 3.39 mmol) in methanol (10 mL) was added conc. HCl (3.5 mL),and the resulting solution was stirred at rt for 16 h. The mixture wasthen concentrated, diluted with water, and the acidity was adjusted topH ˜7 by slow addition of saturated aqueous sodium bicarbonate solution.The mixture was then extracted with dichloromethane, and the combinedorganic layers were washed with saturated sodium chloride solution,dried over sodium sulfate, and concentrated under reduced pressure. Theresidue was then triturated with ethyl acetate/hexane to afford methyl4-(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate(998 mg, 89%). LC-MS ret. time 3.11 min, m/z 329.9 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 1.31 (s, 6H), 3.28 (s, 2H), 3.66 (s, 3H), 6.84 (t, 1H),7.21-7.35 (m, 2H), 7.55 (d, 2H), 7.93 (d, 2H).

Intermediate Q Methyl4-(4′-amino-3′-methyl-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0235]

[0236] 4-Iodo-2-methylphenylformamide

[0237] Step 1. This intermediate was prepared by using a proceduresimilar to that described above for 2-fluoro-4-iodophenylformamide.LC-MS ret. time 2.43 min, m/z 262.0 (MH⁺); ¹H NMR (300 MHz, DMSO-d₆) δ2.14 (s, 3H), 7.49 (dd, 1H), 7.52-7.59 (m, 2H), 8.24 (s, 1H), 9.56 (s,1H).

[0238] Methyl4-[4′-(formylamino)-3′-methyl-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate

[0239] Step 2. This intermediate was prepared by using a proceduresimilar to that described above for methyl4-[3′-fluoro-4′-(formylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoate.LC-MS ret. time 2.78 min, m/z 354.1 (MH⁺); ¹H NMR (300 MHz, DMSO-d₆) δ1.02 & 1.13 (s, 6H 2.22 & 2.28 (s, 3H), 3.36 (s, 2H), 3.51 (s, 3H), 7.29(d) & 7.40 (s) (2H), 7.78 (d, 2H), 7.90 & 7.96 (d, 3H), 8.46 (d) (1H),9.82 (d) (1H).

[0240] Methyl4-(4′-amino-3′-methyl-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0241] Step 3. This intermediate was prepared by using a proceduresimilar to that described above for methyl4-(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate.LC-MS ret. time 2.64 min, m/z 326.1 (MH⁺); ¹H NMR (300 MHz, CDCl₃) δ1.31 (s, 6H), 2.25 (s, 3H), 3.29 (s, 2H), 3.66 (s, 3H), 6.80 (s, 1H),7.35 (s, 2H), 7.60 (d, 2H), 7.93 (d, 2H).

Intermediate R Methyl4-(4′-amino-3′-methoxy-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0242]

[0243] Methyl4-(3′-methoxy-4′-nitro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0244] Step 1. A suspension of methyl4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoate (200 mg, 0.67 mmol),bis(pinacolato)diboron (170 mg, 0.67 mmol), potassium acetate (197 mg,2.01 mmol), and palladium acetate (5 mg, 0.02 mmol) inN,N-dimethylformamide (4.0 mL) was degassed by bubbling a flow of argonfor 30 minutes. The reaction mixture was then heated at 80° C. for 3 h.After the mixture was cooled to rt, 5-chloro-2-nitroanisole (125 mg,0.67 mmol), tetrakis(triphenyl-phosphine)palladium(0) (23 mg, 0.02mmol), and cesium carbonate (327 mg, 1.0 mmol) were added and thereaction mixture was heated at 80° C. for 16 h. The mixture was thencooled to rt, and water was added. The aqueous layer was extracted withethyl acetate and the combined organic phases were dried over anhydroussodium sulfate. Solvent was removed under reduced pressure and theresidue was purified by flash chromatography (Biotage Flash 40M, 1:3ethyl acetate/hexane) to afford methyl4-(3′-methoxy4′-nitro-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate(120 mg, 48%). LC-MS ret. time 3.38 min, m/z 371.8 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 1.19 (s, 6H), 3.36 (s, 2H), 3.51 (s, 3H), 4.02 (s, 3H),7.21-7.24 (m, 2H), 7.64-7.69 (m, 2H), 7.93 (d, 1H), 8.00-8.04 (m, 2H).

[0245] Methyl4-(4′-amino-3′-methoxy-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate

[0246] Step 2. To a solution of methyl4-(3′-methoxy-4′-nitro-1,1′-biphenyl-4-yl)-2,2-dimethyl -4-oxobutanoate(670 mg, 1.80 mmol) in 85% aqueous ethanol (27 mL) was added iron powder(1.01 g, 18.04 mmol) and 2 N aqueous HCl (0.9 mL, 1.8 mmol), and theresulting suspension was heated at reflux for 2.5 h. The mixture wasthen cooled to rt, and filtered through a pad of Celite®. Water wasadded, the mixture was extracted with ethyl acetate, and the combinedorganic phases were dried over anhydrous sodium sulfate. Solvent wasremoved under reduced pressure and the residue was triturated with ethylacetate/hexane to afford methyl4-(4′-amino-3′-methoxy-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate(410 mg, 67%). LC-MS ret. time 2.58 min, m/z 342.1 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 1.31 (s, 6H), 3.28 (s, 2H), 3.66 (s, 3H), 3.90 (s, 3H),6.75 (d, 1H), 7.02-7.09 (m, 2H), 7.59 (d, 2H), 7.94 (d, 2H).

Intermediate S Ethyl4-(4′-amino-3-methyl-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate

[0247]

[0248] 4-Acetyl-3-methylphenyl trifluoromethanesulfonate

[0249] Step 1. To a cooled solution (0-5° C.) of1-(4-hydroxy-2-methylphenyl)ethanone (22.1 g, 0.147 mol) and pyridine(40.0 mL, 0.500 mol) in dichloromethane (100 mL) was slowly addedtrifluoromethanesulfonic anhydride (35.0 mL, 0.207 mol). After theaddition was completed, the ice bath was removed, and the reactionmixture was stirred at rt for 1.5 h. Water (50 mL) was added and thelayers were separated. The organic layer was washed with water (2×20 mL)and 0.5 N aqueous HCl, dried over magnesium sulfate, and concentratedunder reduced pressure. The crude product was purified by flashchromatography (Biotage Flash 75, 10/90 ethyl acetate/hexane) to give4-acetyl-3-methylphenyl trifluoromethanesulfonate as a light yellow oil(40.83 g, 90% yield). GC-MS m/z 282 (M⁺), ret. time 8.20 min ¹H NMR(CDCl₃) δ 2.56 (s, 3H), 2.58 (s, 3H), 7.05-7.14 (m, 2H), 7.78 (d, 1H).

[0250] 1-(3-Methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone

[0251] Step 2. A mixture of 4-acetyl-3-methylphenyltrifluoromethanesulfonate (6.90 g, 24.0 mmol), 4-nitrophenylboronic acid(3.80 g, 24 mmol), 2 N aqueous sodium carbonate (88.0 mL), dioxane (88.0mL), and toluene (296 mL) was purged with argon for 30 minutes before[1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1complex with dichloromethane, 1.90 g, 2.30 mmol) was added. The reactionmixture was heated at 85° C. and stirred overnight. The layers wereseparated and the organic layer was washed with water (2×50 mL), driedover magnesium sulfate, and concentrated under reduced pressure to givea dark brown oil. This material was purified by flash chromatography (7to 20% ethyl acetate/hexane) to give1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid(6.12 g, 99% yield). GC-MS m/z 255 (M⁺), ret. time 9.89 min; ¹H NMR(CDCl₃) δ: 2.61 (s, 3H), 2.62 (s, 3H), 7.49-55 (m, 2H), 7.78 (d, 2H),7.81 (d, 1H), 8.32 (d, 2H).

[0252] 2-Bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone

[0253] Step 3. A mixture of1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone (5.66 g, 22 mmol),pyridinium tribromide (10.63 g, 33.0 mmol), and glacial acetic acid (60mL) was stirred at 110° C. for 3 h. The reaction mixture was cooled to0-5° C., and the precipitated product was collected by filtration andwashed with small amounts of water, ethanol, and diethyl ether. Thecrude material was purified by flash chromatography (5:95 ethylacetate/hexane) to give2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a lightyellow solid (4.33 g, 59% yield). HPLC ret. time 3.63 min; ¹H NMR(CDCl₃) δ: 2.63 (s, 3H), 2.25 (s, 2H), 7.52-7.58 (m, 2H), 7.72-7.83 (m,3H), 8.32 (d, 2H).

[0254] Diethyl2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate

[0255] Step 4. To a cold suspension (0-5° C.) of 95% sodium hydride(3.53 g, 13.0 mmol) in dry tetrahydrofuran (30 mL) was slowly addeddiethyl 2-phenylethylmalonate (3.53 g, 13 mmol). The ice bath wasremoved and the reaction mixture was stirred at rt for 45 minutes. Asolution of 2-bromo-1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone(4.06 g, 12.0 mmol) in dry tetrahydrofuran (50 mL) was slowly added, andthe resulting mixture was stirred at rt for about 70 h. Ethyl acetate(80 mL) and water (20 mL) were added, and the layers were separated. Theorganic layer was washed with water (2×30 mL), dried over magnesiumsulfate, and concentrated under reduced pressure to give a dark, brownoil. This material was purified by flash chromatography (10:90 ethylacetate/hexane) to give diethyl2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonateas a light yellow oil (5.30 g, 82% yield). LC-MS ret. time 4.01 min, m/z517.9 (MH⁺); ¹H NMR (CDCl₃) δ 1.23-1.35 (m, 6H), 2.41-2.50 (m, 2H), 2.56(s, 3H), 2.59-2.66 (m, 3.71 (s, 2H), 4.21-4.32 (m, 4H), 7.13-7.19 (m,3H), 7.22-7.30 (m, 2H), 7.49-7.55 (m, 2H), 7.73-7.82 (m, 3H), 8.31 (d,2H).

[0256] Ethyl4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate.

[0257] Step 5. A mixture of diethyl2-[2-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]-2-(2-phenylethyl)malonate(4.87 g, 9.41 mmol), 1 N aqueous sodium hydroxide (10.4 mL, 10.40 mmol),ethanol (10 mL), and acetone (10 mL) was stirred at 50° C. overnight.The mixture was concentrated and the residue was dissolved indimethoxyethane (20 mL), and stirred at 80° C. overnight. The mixturewas concentrated, and the residue was dissolved in ethyl acetate (30mL). The solution was washed with water (2×5 mL), dried over magnesiumsulfate, and concentrated under reduced pressure. The material obtainedwas purified by flash chromatography (10:90 ethyl acetate/hexane) togive ethyl4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoateas a light yellow oil (3.53 g, 99% yield). LC-MS ret. time 4.18 min, m/z446.0 (MH⁺); ¹H NMR (CDCl₃) δ: 1.33 (t, 3H), 1.83-2.17 (m, 2H), 2.58 (s,3H), 2.67-2.78 (m, 2H), 3.00 (dd, 1H), 3.14 (m, 1H), 3.49 (dd, 1H), 4.09(q, 2H), 7.14-7.36 (m, 5H), 7.47-7.55 (m, 2H), 7.72-7.83 (m, 3H), 8.33(d, 2H).

[0258] Ethyl4-(4′-amino-3-methyl-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate

[0259] Step 6. A mixture of ethyl4-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate(3.40 g, 7.60 mmol), iron powder (4.20 g, 76.00 mmol), 2 N aqueoushydrochloric acid (3.80 mL, 7.60 mmol), and 85/15 ethanol/water (100 mL)was stirred at reflux for 2.5 h. The reaction mixture was filteredthrough a pad of Celite®, and concentrated to give ethyl4-(4′-amino-3-methyl-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoateas a light, brown solid (2.94 g, 93% yield). LC-MS ret. time 3.23 min,m/z 416.1 (MH⁺); ¹H NMR (CDCl₃) δ 1.32 (t, 3H), 1.82-2.17 (m, 2H), 2.58(s, 3H), 2.68-2.77 (m, 2H), 2.98-3.09 (m, 2H), 3.49 (dd, 1H), 3.74 (brs, 2H), 4.10 (q, 2H), 6.79 (d, 2H), 7.12-7.37 (m, 5H), 7.38-7.54 (m,4H), 7.78 (d, 1H).

Intermediate T 3-(4′-Amino-biphenyl-4-carbonyl)-cyclohexanecarboxylicacid methyl ester

[0260]

[0261] 3-(4-Bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester

[0262] Step 1. To a solution oftrans-3-(4-bromobenzoyl)cyclohexane-1-carboxylic acid (500 mg, 1.61mmol, obtained from Rieke Metals Inc., Lincoln, Nebr., USA) and2,2-dimethoxypropane (669 mg, 6.43 mmol) in methanol (20 mL), 5 drops of4 M HCl in dioxane was added, and this reaction mixture was heated at50° C. overnight. The solvent was removed by rotary evaporation to givethe product 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl esteras a brown oil (500 mg, yield 95.7%). ¹H NMR (300 MHz, DMSO) δ 7.80 (d,2H), 7.60 (d, 2H), 3.70 (s, 3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90(m, 4H), 1.70-1.50 (m, 4H); LC-MS ret. time 3.30 min, m/z 324.9 (MH⁺).

[0263] 3-(4′-Amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acidmethyl ester

[0264] Step 2. To a solution of3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester (500 mg,1.54 mmol) and 4-aminophenyl boronic acid (252 mg, 1.85 mmol) in toluene(40 mL) and dioxane (10 mL), 2 N aqueous Na₂CO₃ (10 mL) was added, andthe mixture was degassed by bubbling with a flow of argon for 45minutes. (1,1-Bis(diphenylphosphino)ferrocene)-dichloropalladium (63 mg,0.08 mmol) was added to the mixture, which was then heated at 80° C.overnight. The reaction mixture was cooled to rt, and then filteredthrough a pad of Celite®, rinsing with ethyl acetate. The organic layerwas separated, washed with water and brine, and dried (Na₂SO₄). Thesolvent was removed by rotary evaporation, and the solid residue waspurified by using a Biotage QuadUV flash chromatography system (eluant:3:1 hexane/EtOAc). The product3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl esterwas obtained as a brown solid (200 mg, yield 38.5%). ¹H NMR (300 MHz,DMSO) δ 7.90 (d, 2H), 7.60 (d, 2H), 7.45 (d, 2H), 6.80 (d, 2H), 3.70 (s,3H), 3.25 (m, 1H), 2.50 (m, 1H), 2.20-1.90 (m, 4H), 1.70-1.50 (m, 4H);LC-MS ret. time 3.80 min (method 2), m/z 338.17 (MH⁺).

Preparation of Compounds of Formula (VII) Intermediate U2-Chloro-6-(trifluoromethyl)-1,3-benzothiazole

[0265]

[0266] In a three-necked flask fitted with a condenser, a suspension ofcopper II chloride (370 mg, 2.75 mmol) in acetonitrile (5 mL) wastreated with tert-butyl nitrite (0.41 mL, 3.44 mmol) and stirred at rtfor 10 minutes. A solution of 2-amino-6-trifluoromethylbenzthiazole (500mg, 2.29 mmol) in acetonitrile (1 mL) was then added dropwise. Themixture was heated at 65° C. for 30 minutes, then cooled and dilutedwith an excess of 1 N aqueous hydrochloric acid solution. The mixturewas extracted with ethyl acetate. The organic phase was separated, dried(MgSO₄), and concentrated under reduced pressure. An orange semi-solid(501 mg, 92%) was obtained and used without further purification. ¹H NMR(300 MHz, CDCl₃) δ 8.10-8.05 (m, 2H), 7.74 (d, 1H); LC-MS m/z 238.2(MH⁺), ret. time 3.76 min TLC R_(f)=0.50 (9:1 hexanes/ethyl acetate).

Intermediate V 2-Chloro-4-methyl-1,3-benzothiazole

[0267]

[0268] To a solution containing copper chloride (II) (1.96 g, 14.61mmol) and tri(ethylene glycol) dimethyl ether (6 mL) in acetonitrile(100 mL) was added isoamyl nitrite (2.14 g, 18.27 mmol), and thereaction mixture was stirred at rt for 30 minutes. To this suspensionwas added dropwise a solution of 2-amino-4-methylbenzothiazole (2.0 g,12.18 mmol) in tri(ethylene glycol) dimethyl ether (10 mL). The reactionmixture was stirred at rt for 10 minutes, and then heated at 50° C. for2.5 h. The reaction mixture was cooled to rt, and then poured cautiouslyinto cold aqueous 6 M HCl (400 mL). The solution was extracted withEtOAc. The organic layer was washed with HCl (1.0 M), water, brine,filtered and concentrated in vacuo. The residue was purified by flashchromatography (Biotage Flash 40M) using 5% ethyl acetate in hexane toafford 2-chloro-4-methyl-1,3-benzothiazole (1.6 g, 71%). ¹H NMR (400MHz, CD₂Cl₂) δ 2.70 (s, 3H), 7.32 (m, 2H), 7.64 (m, 1H).

Intermediate W 2-Chloro-4,6-difluoro-1,3-benzothiazole

[0269]

[0270] To a solution containing copper chloride (II) (0.87 g, 6.45 mmol)and tri(ethylene glycol) dimethyl ether (3 mL) in acetonitrile (50 mL)was added isoamyl nitrite (0.94 g, 8.06 mmol), and the reaction mixturewas stirred at rt for 30 minutes. To this suspension was added dropwisea solution of 4,6-difluoro-1,3-benzothiazol-2-amine (1.0 g, 5.37 mmol)in tri(ethylene glycol) dimethyl ether (5 mL). The reaction mixture wasstirred at rt for 10 minutes, and then heated at 50° C. for 2.5 h. Thereaction mixture was cooled to rt, and then poured cautiously into coldaqueous 6 M HCl (200 mL). The solution was extracted with EtOAc. Theorganic layer was washed with HCl (1.0 M), water and brine, filtered andconcentrated down to afford 2-chloro-4,6-difluoro-1,3-benzothiazole (1.1g, 99%). ¹H NMR (400 MHz, DMSO-d₆) 7.05 (m, 1H), 7.36 (m, 1H).

Intermediate X 2-Chloro-6-trifluoromethoxy-1,3-benzothiazole

[0271]

[0272] To a solution containing dry copper (II) chloride (3.44 g, 25.62mmol) and tri(ethylene glycol) dimethyl ether (10 g) in acetonitrile(150 mL) was added isoamyl nitrite (4.5 mL, 32.02 mmol). The reactionmixture was stirred at rt under argon for 30 minutes. To this suspensionwas added dropwise, a solution containing6-trifluoromethoxy-1,3-benzothiazol-2-ylamine (5 g, 21.35 mmol) andtri(ethylene glycol) dimethyl ether (10 g). The reaction mixture wasstirred at rt for 10 minutes, and then heated at 50° C. for 3 h. Themixture was cooled to rt, poured cautiously into aqueous 6 N HCl, andextracted with ethyl acetate. The organic layer was washed with 1Naqueous HCl and brine, and concentrated under reduced pressure to givethe desired compound in near-quantitative yield, which was used withoutfurther purification in the next step.

Intermediate Y 2-Chloro-5,7-difluoro-1,3-benzothiazole

[0273]

[0274] N-(3,5-Difluorophenyl) thiourea

[0275] Step 1. Benzoyl chloride (5.44 g, 38.73 mmol) was added to astirred solution of ammonium thiocyanate (3.83 g, 50.35 mmol) in acetone(80 mL) at 30° C. The mixture was stirred at reflux for 30 minutes, thencooled to 50° C., and a solution of 3,5-difluoroaniline (5.00 g, 38.73mmol) in acetone (10 mL) was added in one portion. The mixture wasstirred at reflux for 30 minutes. A solution of NaOH (5.42 g, 135.54mmol) in water (65 mL) was added, and the mixture was stirred at refluxfor 20 minutes and then cooled to 20° C. Concentrated HCl was added toadjust the acidity to pH=5, and then the mixture was adjusted toslightly alkaline by the addition of conc. ammonium hydroxide. After 30minutes, the mixture was cooled to 10° C. and extracted with EtOAc, andthe combined organic layer was washed with brine, filtered, andconcentrated to afford N-(3,5-difluorophenyl) thiourea (3.52 g, 48%).ret. time 1.73; m/z 189.0 (MH⁺); ¹H NMR (400 MHz, MeOH-d₄) δ 6.72 (m,1H), 7.16 (m, 2H).

[0276] 5,7-Difluoro-1,3-benzothiazol-2-amine

[0277] Step 2. To a suspension of N-(3,5-difluorophenyl) thiourea (3.40g, 18.07 mmol) in DCE (95 mL) was added a solution of bromine in DCE (5mL) below 30° C. The mixture was heated at reflux for 2.5 h, then cooledto 10° C., and the precipitate formed was collected by filtration andwashed with DCE. The solid was stirred with water (200 mL), basified bytreatment with conc. ammonium hydroxide, filtered, and dried in a vacuumoven to afford 5,7-difluoro-1,3-benzothiazol-2-amine (3.05 g, 90%). ret.time 2.18; m/z 187.1 (NH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 6.92 (m, 1H),7.00 (m, 2H), 7.92 (s, 2H).

[0278] 2-Chloro-5,7-difluoro-1,3-benzothiazole

[0279] Step 3. To a solution containing copper chloride (H) (0.89 g,6.64 mmol) and tri(ethylene glycol) dimethyl ether (6 mL) inacetonitrile (60 mL) was added isoamyl nitrite (0.97 g, 8.30 mmol) andthe reaction mixture was stirred at rt for 30 minutes. To thissuspension was added dropwise a solution of5,7-difluoro-1,3-benzothiazol-2-amine (1.03 g, 5.53 mmol) intri(ethylene glycol) dimethyl ether (20 mL) and acetonitrile (30 mL).The reaction mixture was stirred at rt for 10 minutes and heated at 50°C. for 2.5 h. The reaction mixture was cooled to rt, and then pouredcautiously into cold aqueous 6 M HCl (400 mL). The solution wasextracted with EtOAc. The organic layer was washed with HCl (1.0 M),water and brine, filtered, and concentrated. The residue was purified byflash chromatography (Biotage Flash 40M) using 5% ethyl acetate inhexane to afford 2-chloro-5,7-difluoro-1,3-benzothiazole (0.55 g, 48%).¹H NMR (400 MHz, CD₂Cl₂) 7.02 (m, 1H), 7.52 (m, 1H).

[0280] In a similar manner to the procedures described above, additional2-chloro-1,3-benzothiazoles were prepared from the corresponding2-amino-1,3-benzothiazoles, such as:

[0281] (a) 2-chloro-6-ethoxy-1,3-benzothiazole (LC-MS m/z 214.2 (MH⁺),ret. time 3.09 min);

[0282] (b) 2-chloro-6-fluoro-1,3-benzothiazole (HPLC ret. time 2.85min);

[0283] (c) 2-chloro-6-methyl-1,3-benzothiazole (LC-MS m/z 184.2 (MH⁺),ret. time 3.09 min);

[0284] (d) 2-chloro-5,7-dimethyl-1,3-benzothiazole (LC-MS m/z 198.1(MH⁺), ret. time 3.36 min);

[0285] (e) 2-chloro-5,6-dimethyl-1,3-benzothiazole (LC-MS m/z 198.2(MH⁺), ret. time 3.34 min);

[0286] (f) 2-chloro-6-methylsulfonyl-1,3-benzothiazole (HPLC ret. time2.18 min); and

[0287] (g) 2-chloro-5,7-difluoro-1,3-benzothiazole (TLC Rf 0.65, 40%EtOAc in hexane).

[0288] In certain cases the requisite 2-amino-1,3-benzothiazole wasprepared from the corresponding thiourea as described above for thepreparation of N-(3,5-difluorophenyl) thiourea and5,7-difluoro-1,3-benzothiazol-2-amine.

Intermediate Z 2-Chloro-5-fluoro-1,3-benzothiazole

[0289]

[0290] Sulfuryl chloride (50 μL, 0.65 mmol) was added neat to5-fluoro-1,3-benzothiazole-2-thiol (100 mg, 0.54 mmol). The mixture wasstirred at ambient temperature for 1 h, then heated at 60° C. for 30minutes. The resulting solution was cooled to rt, and poured onto ice.The title compound was collected by filtration, washed with water, anddried under vacuum. The solid obtained was used without furtherpurification; LC-MS m/z 188.1 (MH⁺), ret. time 3.27 min.

Intermediate AA 2-Chloro-5-(trifluoromethyl)benzothiazole

[0291]

[0292] 2-Mercapto-5-(trifluoromethyl)benzothiazole

[0293] Step 1. To a mixture of sodium hydride (0.98 g, 40.91 mmol) anddiethylene glycol monoethyl ether (25 mL) was added2-chloro-5-(trifluoromethyl)aniline (5.00 g, 25.57 mmol) under anitrogen atmosphere. The resulting mixture was stirred at rt for 30minutes, and then carbon disulfide (3.89 g, 51.13 mmol) was added. Thereaction mixture was then heated at 140° C. for 6 hours. After coolingthe solution to rt, the product was precipitated by addition of conc.HCl, collected by filtration, and recrystallized from isopropyl ether toafford 2-mercapto-5-(trifluoromethyl)benzothiazole (2.65 g, 44%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.61 (d, 1H), 7.94 (d, 1H).

[0294] 2-Chloro-5-(trifluoromethyl)benzothiazole

[0295] Step 2. Sulfuryl chloride (9.09 g, 67.33 mmol) was added withstirring to 2-mercapto-5-(trifluoromethyl)benzothiazole (2.64 g, 11.22mmol) over a period of 5 minutes. The reaction mixture was then allowedto stand for approximately 1 h. Ice water was added to the reactionmixture with stirring to decompose the excess of sulfuryl chloride, andthe product was then extracted with ethyl acetate. The organic layer waswashed with water (3×) and brine, dried over anhydrous Na₂SO₄ andconcentrated. The resulting solid was dissolved in EtOAc and filteredthough a short silica-gel column, eluting with EtOAc, to give2-chloro-5-(trifluoromethyl)benzothiazole (2.50 g, 94%). LC-MS m/z 238.0(MH⁺), ret. time 2.55 min; ¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (d, 1H),8.38 (m, 2H).

Intermediate BB 2-Chloro-6-(trifluoromethyl)benzothiazole

[0296]

[0297] 2-Mercapto-6-(trifluoromethyl)benzothiazole

[0298] Step 1. A mixture of 2-chloro-4-trifluoromethylaniline (15.0 g,76.7 mmol) and potassium O-ethyl dithiocarbonate (29.5 g, 184.1 mmol) in75 mL anhydrous.DMF was heated at 130° C. overnight under a nitrogenatmosphere. The reaction mixture was cooled to rt, and then 1 N HClsolution (200 mL) was added with stirring to induce precipitation. Afterthe mixture was stirred for 30 minutes, the solid precipitate wascollected by filtration and rinsed with water. The filter cake wasdissolved in 100 mL EtOAc, and the solution was dried over Na₂SO₄. EtOAcwas removed by rotary evaporation, and the residue was dried in vacuo toafford the desired product as a white solid (18.0 g, 99%). ¹H NMR(DMSO-d₆) δ 14.00 (bs, 1H), 8.20 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H);GC-EIMS m/z 235 (M⁺).

[0299] 2-Chloro-6-(trifluoromethyl)benzothiazole

[0300] Step 2. Sulfuryl chloride (40 mL) was added with stirring to2-mercapto-6-(trifluoromethyl) benzothiazole (18.0 g, 76.7 mmol) at <20°C. under a nitrogen atmosphere, and the suspension was then stirred atrt for 2 h. The reaction mixture was poured into ice water withstirring. Precipitation was formed, and stirring was continued for 2 h.The solid precipitate was filtered, and rinsed with water. The wetfilter cake was dissolved in 100 mL EtOAc, and the solution was washedwith 100 mL water and 50 mL saturated aqueous NaHCO₃ solution, thendried over Na₂SO₄. EtOAc was removed by rotary evaporation, and theresidue was dried in vacuo to afford the desired product as a lightyellow solid (16.5 g, 91%). GC-EIMS m/z 237 (M⁺); ¹H NMR (CDCl₃) δ 8.10(s, 1H), 8.00 (d, 1H), 7.70 (d, 1H).

[0301] In a similar manner to the procedures described above, additional2-chloro-1,3-benzothiazoles were prepared from the corresponding2-mercapto-1,3-benzothiazoles, such as2-chloro-5-fluoro-1,3-benzothiazole (LC-MS m/z 188.1 (MH⁺), ret. time3.27 min). Additional 2-chloro-1,3-benzothiazoles were commerciallyavailable, such as 2-chloro-benzothiazole, 2,6-dichlorobenzothiazole,2,4-dichlorobenzothiazole, 2-chloro-6-methoxy-1,3-benzothiazole,2-chloro-5-methoxy-1,3-benzothiazole, and2-chloro-6-nitro-1,3-benzothiazole. Certain 2-bromo-thiazoles werecommercially available, such as 2-bromo-thiazole and2-bromo-5-nitro-thiazole.

Intermediate CC 5-Chloro-2-methanesulfonylbenzothiazole

[0302]

[0303] 5-Chloro-2-methylsulfanyl-benzothiazole

[0304] Step 1. To 5-chlorobenzothiazole-2-thiol (1.00 g, 4.96 mmol) inanhydrous tetrahydrofuran (20 mL) was added powdered potassium carbonate(1.37 g, 9.92 mmol) as a solid. Iodomethane (0.62 mL, 1.41 g, 9.92 mmol)was then added neat to the mixture, with rapid stirring. After stirringfor 18 h, solids were removed by filtration. The filtrate wasconcentrated under vacuum to provide the title compound as a waxy yellowsolid (1.0 g, 93%). ¹H NMR (300 MHz, CDCl₃) δ 7.77 (s, 1H), 7.57 (d,1H), 7.21-7.17 (m, 1H), 2.72 (s, 3H); LC-MS m/z 216.2 (MH⁺), retentiontime 3.20 minutes. TLC R_(f) 0.72 (2:1 hexanes/ethyl acetate).

[0305] 5-Chloro-2-methanesulfonylbenzothiazole

[0306] Step 2. To a 0° C. solution of5-chloro-2-methylsulfanyl-benzothiazole (1.00 g, 4.64 mmol) indichloromethane (25 mL) was added 3-chloroperoxybenzoic acid (50%, 3.20g, 9.27 mmol). The solution was stirred at rt for 24 h, and saturatedaqueous Na₂S₂O₅ solution was added to destroy any unreacted peracid. Thelayers were separated, and the organic layer was washed with saturatedaqueous sodium bicarbonate solution and brine, then dried (MgSO₄) andconcentrated under reduced pressure to a yellow solid. The crude solidwas triturated with hexanes, collected by filtration, and air-dried toprovide the title compound as a pale yellow solid (0.96 g, 83%). ¹H NMR(300 MHz, CDCl₃) δ 8.17 (s, 1H), 8.04 (d, 1H), 7.41 (dd, 1H), 3.40 (s,3H); LC-MS m/z 248.0 (MH⁺), retention time 3.05 minutes. TLC R_(f) 0.36(2:1 hexanes/ethyl acetate).

Intermediate DD 6-Methyl-2-(methylsulfonyl)-1,3-benzoxazole

[0307]

[0308] 6-Methyl-1,3-benzoxazole-2(3H)-thione

[0309] Step 1. A mixture of 6-amino-m-cresol (593.7 mg, 4.82 mmol) andpotassium O-ethyl xanthate (850 mg, 5.30 mmol) in pyridine (10 mL) wasstirred and heated to reflux for 2 h. It was cooled to rt, poured into amixture of ice-water (40 mL), and concentrated HCl (4 mL). The solid wascollected, washed with water, and dried in the hood overnight and thenin a vacuum oven at 45° C. for 3 h. The product6-methyl-1,3-benzoxazole-2(3H)-thione was obtained as beige powder (735mg, yield 92.3%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.10 (s, 1H), 7.03 (d,2H), 2.42 (s, 3H); LC-MS ret. time 2.37 min (method 2), m/z 166.0 (MH⁺).

[0310] 6-Methyl-2-(methylsulfanyl)-1,3-benzoxazole

[0311] Step 2. 6-Methyl-1,3-benzoxazole-2(3H)-thione (375 mg, 2.27 mmol)was dissolved in THF (2.0 mL), and iodomethane (1610.8 mg, 11.35 mmol)and potassium carbonate (627.36 mg, 4.54 mmol) were added. This reactionmixture was stirred vigorously at rt overnight. The reaction mixture wasfiltered and the solid was rinsed with additional THF. The filtrate wasconcentrated in vacuo to a yellow solid. The solid was partitionedbetween ethyl acetate and water. The organic layer was separated andwashed with brine, dried with MgSO₄, and concentrated. The solid wasdried for 1 h in a 50° C. oven. The product6-methyl-2-(methylsulfanyl)-1,3-benzoxazole was obtained as yellow solid(145 mg, 35.6%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.50 (d, 1H), 7.20 (s, 1H),7.10 (d, 1H), 2.78 (s, 3H), 2.42 (s, 3H); LC-MS ret. time 2.90 min(method 2), m/z 180.1 (MH⁺).

[0312] 6-Methyl-2-(methylsulfonyl)-1,3-benzoxazole

[0313] Step 3. meta-Chloroperoxybenzoic acid (1.37 g, 6.14 mmol) wasadded to a solution of 6-methyl-2-(methylsulfanyl)-1,3-benzoxazole (500mg, 2.79 mmol) in dichloromethane (20 mL) at 0° C. The reaction waswarmed to rt and stirred at rt for a total of 48 h. The reaction wastransferred to a separatory funnel, washed with saturated aqueous NaHCO₃(3×5 mL) and brine (10 mL), dried with MgSO₄, and concentrated withoutheating. The product 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (200mg, 33.9%) was obtained as pale yellow solid. GC-MS ret. time 10.53 min,m/z 211 (MH⁺).

[0314] In a similar manner to the preceding example, the following2-(methylsulfonyl)-1,3-benzoxazoles were prepared:

[0315] (a) 6-chloro-2-(methylsulfonyl)-1,3-benzoxazole;

[0316] (b) 6-methoxy-2-(methylsulfonyl)-1,3-benzoxazole;

[0317] (c) 5-methyl-2-(methylsulfonyl)-1,3-benzoxazole;

[0318] (d) 4-methyl-2-(methylsulfonyl)-1,3-benzoxazole;

[0319] (e)2-(methylsulfonyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]oxazole;

[0320] (f) 5-fluoro-2-(methylsulfonyl)-1,3-benzoxazole;

[0321] (g) 6-fluoro-2-(methylsulfonyl)-1,3-benzoxazole;

[0322] (h) 5-isopropyl-2-(methylsulfonyl)-1,3-benzoxazole;

[0323] (i) 5-n-propyl-2-(methylsulfonyl)-1,3-benzoxazole; and

[0324] (j) 5,6-dimethyl-2-(methylsulfonyl)-1,3-benzoxazole.

Intermediate EE 2-Chloro-5,6-difluoro-1H-benzimidazole

[0325]

[0326] 5,6-Difluoro-1H-benzimidazol-2-amine

[0327] Step 1. The procedure used was similar to that reported in J.Med. Chem. 40:811-818, 1997. A solution of1,2-diamino-4,5-difluorobenzene (500 mg, 3.47 mmol) in water (5 mL) wascooled to 0° C. and then treated with a solution of cyanogen bromide(0.83 mL, 4.16 mmol, 5 M in acetonitrile) and solid sodium bicarbonate(583 mg, 6.94 mmol). The solution was stirred at rt overnight and wasthen concentrated in vacuo. The dark residue was suspended in ethanoland heated at reflux for 15 minutes. The hot suspension was filtered,rinsing with hot ethanol, and the filtrate was concentrated in vacuo toafford 5,6-difluoro-1H-benzimidazol-2-amine (580 mg, 59%), which wasused in the next step without further purification. LC-MS m/z 170.2(MH⁺), ret. time 0.85 min; ¹H NMR (300 MHz, DMSO-d₆) δ 6.30 (br s, 2H),7.06 (dd, 2H), 10.79 (br s, 1H).

[0328] 2-Chloro-5,6-difluoro-1H-benzimidazole

[0329] Step 2. The procedure used was similar to that reported in J.Med. Chem. 40:811-818, 1997. To a mixture of copper(II) chloride (795mg, 5.91 mmol) in acetone (20 mL) was added tert-butyl nitrite (0.53 mL,4.43 mmol). The reaction mixture was stirred at rt for 20 minutes,5,6-difluoro-1H-benzimidazol-2-amine (500 mg, 2.96 mmol) was then added,and the mixture was heated at reflux for 2 h (with additional portionsof tert-butyl nitrite added every 0.5 h). The reaction mixture was thencooled to rt, treated with 2 N HCl, and extracted with ethyl acetate.The organic phase was dried over sodium sulfate and concentrated invacuo to afford 2-chloro-5,6-difluoro-1H-benzimidazole (580 mg, 73%),which was used without further purification in the next step. LC-MS m/z189.2 (MH⁺), ret. time 1.96 min; ¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (t,2H), 13.5 (br s, 1H).

[0330] Certain 2-chlorobenaimidazoles were commercially available suchas 2-chlorobenzimidazole and 2-chloro-5-methoxybenzimidazole.

Preparation of Compounds of Formula (IX) Intermediate FFN-(4-Bromophenyl)-6-(trifluoromethyl)-1H-benzimidazol-2-amine

[0331]

[0332] 1,2-Diamino-5-trifluoromethylbenzene (0.25 g, 1.42 mmol) wasdiluted in toluene (5 mL) and treated with 4-bromophenylisothiocyanate(0.30 g, 1.42 mmol). The dark solution was stirred at 100° C. for 15minutes, then treated with 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13mmol). The reaction was maintained at 100° C. for 5 h. The reaction wasconcentrated and partitioned between ethyl acetate and water. Theorganic layer was separated, dried (MgSO₄), and concentrated underreduced pressure. The dark brown oil was purified by flashchromatography on silica gel, eluting with a gradient from 9:1hexanes/ethyl acetate to 100% ethyl acetate. The title compound wasobtained as a light pink solid (0.50 g, 30%). ¹H NMR (300 MHz, DMSO-d₆)δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d, 1H),7.55-7.42 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH⁺), retentiontime 2.33 minutes.

Intermediate GGN-(4-Bromo-2-fluorophenyl)-N-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]amine

[0333]

[0334] 1,2-Diamino-5-trifluoromethylbenzene (0.50 g, 2.84 mmol) wasdiluted in dichloromethane (5 mL) and treated with4-bromo-2-fluoro-phenylisothiocyanate (0.66 g, 2.84 mmol). The darksolution was stirred at 45° C. for 15 minutes, then1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol) was added all at once.The reaction was heated in a 45° C. oil bath overnight, then cooled andconcentrated at reduced pressure. The dark residue was diluted withethyl acetate, and the organic layer was washed with water. The organiclayer was dried (MgSO₄) and concentrated in vacuo. The resulting darkbrown oil was purified by flash chromatography on silica gel eluted on agradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The titlecompound was collected as a light pink solid (0.60 g, 57%). ¹H NMR (300MHz, DMSO-d₆) δ 11.3 (broad d, 1H), 9.87 (d, 1H), 7.50 (d, 2H), 7.61 (d,1H), 7.55-7.41 (m, 3H), 7.35-7.30 (m, 1H); LC/MS m/z 356.2 (MH⁺),retention time 2.33 minutes.

Intermediate HH N-(4-Iodophenyl)6-methyl-1,3-benzothiazol-2-amine

[0335]

[0336] N-(4-Iodophenyl)-N′-(4-methylphenyl) thiourea

[0337] Step 1. A solution of p-tolyl thiocyanate (0.65 g, 4.35 mmol) andp-iodo-aniline (1.00 g, 4.57 mmol) in EtOH was heated at reflux for 3 h.Then the reaction mixture was diluted with EtOH and the precipitate wascollected by filtration, washed with EtOH and ether, and dried in avacuum oven to give N-(4-iodophenyl)-N′-(4-methylphenyl) thiourea (1.32g, 90% purity, 74% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.78 (s, 3H),7.12 (d, 2H), 7.29 (m, 4H), 7.63 (m, 2H), 9.72 (s, 1H), 9.76 (s, 1H).

[0338] N-(4-Iodophenyl)-6-methyl-1,3-benzothiazol-2-amine

[0339] Step 2. A suspension of N-(4-iodophenyl)-N′-(4-methylphenyl)thiourea (0.62 g, 4.68 mmol) in chloroform (23 mL) was treated with asolution of bromine (2.65 g, 16.59 mmol) in chloroform (1 mL). Thereaction mixture was stirred at rt for 5 minutes and then heated at 50°C. for 5 minutes. Then the reaction mixture was allowed to cool, and wastreated with sulphurous acid until the orange color disappeared. Thereaction mixture was neutralized by treatment with conc. ammoniumhydroxide. More chloroform was then added to dissolve the precipitate.The layers was separated, and the organic layer was washed with waterand brine, dried over sodium sulfate, filtered and, concentrated to giveN-(4-iodophenyl)-6-methyl-1,3-benzothiazol-2-amine (0.6 g, 97%). ¹H NMR(400 MHz, DMSO-d₆) δ 2.36 (s, 3H), 7.12 (m, 1H), 7.48 (d, 1H), 7.60 (m,3H), 7.65 (m, 2H), 10.50 (s, 1H).

Intermediate IIN-(4-Bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine

[0340]

[0341] To a solution of 2-chloro-4-methyl-1,3-benzothiazole (0.25 g,1.36 mmol) in n-BuOH (8 mL) was added 4-bromo-2-fluoroaniline (0.52 g,2.72 mmol) and HCl (4.0 M in dioxane, 0.5 mL). The reaction was heatedat 90° C. overnight. Solvent was removed by rotary evaporation and 1 Naqueous HCl was added. The aqueous layer was separated and extractedwith EtOAc. The combined organic phases were washed with 1 N aqueous HCland brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was brought up in MeOH and the precipitate was collected byfiltration, washed with MeOH, and dried in a vacuum oven to giveN-(4-bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine (0.41 g,89%). ¹H NMR (400 MHz, DMSO-d₆) δ 2.62 (s, 3H), 7.07 (t, 1H), 7.15 (d,1H), 7.36 (m, 2H), 7.51 (d, 1H), 8.72 (t, 1H).

Intermediate JJN-(4-Bromo-2-fluorophenyl)-N-(6-trifluoromethoxy-1,3-benzothiazo-1-2-yl)amine

[0342]

[0343] In a 250-mL round-bottom flask,2-chloro-6-trifluoromethoxy-1,3-benzothiazole (5.36 g, 21.14 mmol) and4-bromo-2-fluoroaniline (4.82 g, 25.36 mmol) were combined in 100 mLn-butanol containing 1% 4.0 M HCl in dioxane, and heated at 90° C.overnight. The mixture was cooled to rt and the solvent was removedunder reduced pressure. Ethyl acetate (50 mL) was added, and the mixturewas ultrasonicated by suspending the flask in an ultrasonication bathfor 30 minutes. The mixture was filtered, and the filtrate wasconcentrated under reduced pressure. Acetonitrile (50 mL) was added tothe mixture, which was then ultrasonicated for 30 minutes and thenfiltered to provide the product as a white solid (5 g, 58%). LC-MS m/z409.1 (MH⁺), ret. time 4.02 min.

Intermediate KKN-(4-Bromo-2-fluorophenyl)-N-(6-fluoro-1,3-benzothiazol-2-yl)amine

[0344]

[0345] In a similar manner to that described above for the preparationof N-(4-bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine andN-(4-bromo-2-fluorophenyl)-N-(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amine,using 2-chloro-6-fluoro-1,3-benzothiazole and 2-fluoro-4-bromoaniline,was prepared the desired product as a white solid (78% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 8.60 (t, 1H), 7.80 (d, 1H), 7.60 (m,2H), 7.40 (d, 1H), 7.20 (m, 1H).

[0346] In a similar manner to the procedures described above, thefollowing N-(4-bromophenyl)-N-(1,3-benzothiazol-2-yl)amines wereprepared from the appropriate 4-bromoanilines and2-chloro-1,3-benzothiazoles:

[0347] (a)N-(4-bromophenyl)-N-(5-trifluoromethyl-1,3-benzothiazol-2-yl)amine(LC-MS m/z 373.0 (MH⁺), ret. time 3.92 min);

[0348] (b)N-(4-bromo-2-fluorophenyl)-N-(5-trifluoromethyl-1,3-benzothiazol-2-yl)amine(LC-MS m/z 391.0 (MH⁺), ret. time 4.04 min (method 2));

[0349] (c)N-(4-bromo-2-fluorophenyl)-N-(6-trifluoromethyl-1,3-benzothiazol-2-yl)amine(LC-MS m/z 391.0 (MH⁺), ret. time 3.95 min);

[0350] (d)N-(4-bromo-2-fluorophenyl)-N-(5,7-dimethyl-1,3-benzothiazol-2-yl)amine(LC-MS m/z 353.1 (MH⁺), ret. time 4.09 min);

[0351] (e)N-(4-bromo-2-fluorophenyl)-N-(5,7-difluoro-1,3-benzothiazol-2-yl)amine(LC-MS m/z 359.1 (MH⁺), ret. time 3.86 min);

[0352] (f)N-(4-bromo-2-fluorophenyl)-N-(6-methoxy-1,3-benzothiazol-2-yl)amine(LC-MS m/z 353.2 (MH⁺), ret. time 3.55 min);

[0353] (g) N-(4-bromo-2-fluorophenyl)-N-(1,3-benzothiazol-2-yl)amine(LC-MS m/z 323.1 (MH⁺), ret. time 3.55 min);

[0354] (h) N-(4-bromophenyl)-N-(6-isopropyl-1,3-benzothiazol-2-yl)amine(LC-MS m/z 347.2 (MH⁺), ret. time 4.44 min); and

[0355] (i)N-(4-bromo-2-fluorophenyl)-N-(6-isopropyl-1,3-benzothiazol-2-yl)amine(LC-MS m/z 365.2 (MH⁺), ret. time 4.57 min).

Intermediate LLN-(4-Iodo-2-fluorophenyl)-6-chloro-1,3-benzothiazol-2-amine

[0356]

[0357] A mixture of 2,6-dichlorobenzothiazole (1.0 g, 4.9 mmol) and2-fluoro-4-iodoaniline (2.32 g, 9.8 mmol) in 20 mL BuOH was stirred at90° C., and then HCl (4 M in dioxane, 1.0 mL) was added. The reactionmixture was stirred with heating at 90° C. overnight, under argon. NMRanalysis then showed little 2,6-dichlorobenzothiazole remaining. AfterBuOH was removed by rotary evaporation, EtOAc (100 mL) and 1 N aqueousHCl (100 mL) were added. The organic layer was separated and washed with1 N aqueous HCl (100 mL), saturated Na₂O₂S₃ solution (50 mL), water (100mL), and then dried over Na₂SO₄. Removal of solvent under reducedpressure afforded a residue, which was triturated with EtOAc (10 mL) andhexanes (40 mL). The solid was filtered and dried in vacuo to a constantweight, to afford the desired product as a light purple solid (0.75 g,38%). ¹H NMR (DMSO-d₆) δ 10.45 (s, 1H), 8.35 (t, 1H), 7.95 (s, 1H), 7.70(d, 1H), 7.58 (d, 2H), 7.30 (d, 1H).

Intermediate MM N-(4-Bromophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine

[0358]

[0359] In a 250-mL round-bottom flask, 1-bromo-4-isothiocyanatobenzene(4.28 g, 20 mmol) and 2-amino-4-methyl-phenol (2.46 g, 20 mmol) werestirred in 120 mL ethanol at rt overnight. The formation ofN-(4-bromophenyl)-N′-(2-hydroxy-5-methylphenyl)thiourea was confirmed byLC-MS. To the mixture, 1.5 eq.1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) wasadded, and the reaction was stirred at rt for another 2 h. The reactionmixture was then heated at reflux for 6 h. The mixture was cooled to rtand the solvent was removed under reduced pressure. The solid wasdissolved in EtOAc and washed with 2 N aqueous HCl and H₂O. The organiclayer was dried (MgSO₄) and the solvent was removed under reducedpressure. The solid obtained was ultrasonicated in 30 mL ether andfiltered to give the desired compound (3.64 g, 60%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.70 (s, 1H), 7.70 (m, 2H), 7.55 (m, 2H), 7.35 (d, 1H), 7.25(s, 1H), 6.95 (d, 1H), 2.40 (s, 3H). LC-MS m/z 303.3 (MH⁺), ret. time3.46 min.

Intermediate NNN-(4-Bromophenyl)-5-(trifluoromethyl)-1,3-benzoxazol-2-amine

[0360]

[0361] 2-Amino-4-(trifluoromethyl)phenol

[0362] Step 1. To a suspension of palladium hydroxide (3.05 g, 21.7mmol) in methanol was added a methanol solution of2-nitro-4-(trifluoromethyl)phenol (1.00 g, 4.8 mmol) followed by solidammonium formate (3.04 g, 48.3 mmol). The mixture was heated at 85° C.and monitored by TLC. The completed reaction was allowed to cool to rtand was filtered through a pad of Celite®, washing with ethyl acetate.The filtrate was concentrated under reduced pressure to provide thetitle compound (0.58 g, 67%). LC-MS m/z 178.1 (MH⁺), retention time 0.55minutes.

[0363] N-(4-Bromophenyl)-5-(trifluoromethyl)-1,3-benzoxazol-2-amine

[0364] Step 2. 2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and1-bromo-4-isothio-cyanatobenzene (302 mg, 1.41 mmol) were stirred inethyl alcohol at ambient temperature for 18 h. The flask was chargedwith 1-[3-(dimethylamino)propyl]-3-ethylcarhodiimide hydrochloride(EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h beforebeing heated at reflux overnight. The reaction was allowed to cool to rtand was concentrated under reduced pressure. The residue was dissolvedin ethyl acetate and washed with 2 N aqueous hydrochloric acid solutionand water, dried (Na₂SO₄), and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel, eluting with 85:15hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MSm/z 357.1 (MH⁺), retention time 4.20 minutes.

Intermediate OON-(4-Bromo-2-fluorophenyl)-5(trifluoromethyl-1,3-benzoxazol-2-amine

[0365]

[0366] 2-Amino-4-(trifluoromethyl)phenol (580 mg, 3.25 mmol) and4-bromo-2-fluoro-1-isothio-cyanatobenzene (750 mg, 3.25 mmol) werestirred in ethyl alcohol at ambient temperature for 18 h. The flask wascharged with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirredfor 2 h before being heated at reflux overnight. The reaction wasallowed to cool to rt and was concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate and washed with 2 N aqueoushydrochloric acid solution and water, dried (Na₂SO₄), and concentratedin vacuo. The crude material was suspended in ether, sonicated, and theresulting solid was collected by filtration to provide the titlecompound (214 mg, 18%). LC-MS m/z 375.1 (MH⁺), retention time 3.70minutes.

[0367] In a similar manner to the procedures described above, thefollowing N-(4-bromophenyl)-N-(1,3-benzoxazol-2-yl)amines were preparedfrom the appropriate 4-bromo-1-isothiocyanatobenzene and 2-aminophenol:

[0368] (a)N-(4-bromo-2-fluorophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine (LC-MSm/z 321.2 (MH⁺), ret. time 3.69 min);

[0369] (b) N-(4-bromophenyl)-N-(6-methyl-1,3-benzoxazol-2-yl)amine(LC-MS m/z 303.2 (MH⁺), ret. time 3.49 min).

Preparation of Compounds of Formula (I) EXAMPLE 14-[4′-(1,3-Benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid

[0370]

[0371] In a 8-mL screw-cap vial, a mixture of methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (60 mg, 0.19mmol) and 2chloro-1,3-benzothiazole (40 mg, 0.23 mmol) in 3 mL n-butanolwere heated at 90° C. overnight. The formation of methyl4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoatewas monitored by LC-MS. The solvent was removed under reduced pressure.The residue was dissolved in 2 mL tetrahydrofuran/dioxane (1:1), and 3equivalents of 1 N aqueous sodium hydroxide was added to the solution.The mixture was shaken at rt overnight and then at 50° C. for 2 h. Theprogress of the hydrolysis reaction was monitored by LC-MS. A solutionof 1N aqueous HCl (3.1 equivalents) was then added to the mixture, andthe solvent was removed under reduced pressure. The residue wasredissolved in 2 mL methanol and a minimum amount of DMF, and theproduct was isolated and purified by preparative reverse-phase HPLC(water/acetonitrile gradient, containing 0.1% TFA) to give 40 mg of4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid (Yield: 45%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (bs, 1H), 10.65 (s,1H), 8.00 (d, 2H), 7.90 (d, 2H), 7.80 (m, 5H), 7.60 (d, 1H), 7.35 (t,1H), 7.20 (t, 1H), 3.30 (s, 2H), 1.10 (s, 6H); LC-MS m/z 431.2 (MH⁺),ret. time 3.40 min.

EXAMPLE 24-[4′-(1H-Benzimidazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid

[0372]

[0373] This compound was prepared from methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (64 mg, 0.21mmol) and 2-chloro-1H-benzimidazole (37.6 mg, 0.25 mmol) in a similarmanner to the method described for4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid, providing 40.7 mg (48%) of the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ 12.00 (br s, 1H), 11.05 (br s, 1H), 8.05 (d, 2H), 7.85 (m,4H), 7.65 (d, 2H), 7.40 (m, 2H), 7.10 (m, 2H), 3.35 (s, 2H), 1.25 (s,6H). LC-MS m/z 414.3 (MH⁺), ret. time 2.27 min.

EXAMPLE 32,2-Dimethyl-4-oxo-4-[4′-(1,3-thiazol-2-ylamino)-1,1′-biphenyl-4-yl]butanoicacid

[0374]

[0375] This compound was prepared from methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (64 mg, 0.21mmol) and 2-bromothiazole (41 mg, 0.25 mmol) in a similar manner to themethod described for4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid, providing 18.6 mg (24%) of the desired product. LC-MS m/z 381.4(MH⁺), ret. time 2.53 min.

EXAMPLE 44-{4′-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxo-2-(2-phenylethyl)butanoicacid

[0376]

[0377] This compound was prepared from methyl4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (78 mg,0.20 mmol), 2,6-dichloro-1,3-benzothiazole (61.6 mg, 0.30 mmol) in asimilar manner to the method described for4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid, providing 26.7 mg (25%) of the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ 10.80 (br s, 1H), 7.75-8.05 (m, 9H), 7.60 (d, 1H), 7.10-7.40(m, 6H), 3.50 (q, 1H), 3.10 (m, 1H), 2.85 (m, 1H), 2.65 (m, 2H), 1.80(m, 2H). LC-MS m/z 541.3 (MH⁺), ret. time 4.07 min.

EXAMPLE 52-(2-{4′-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-oxoethyl)pentanoicacid

[0378]

[0379] This compound was prepared from methyl2-[2-(4′-amino-1,1′-biphenyl-4-yl)-2-oxoethyl]-pentanoate (68 mg, 0.20mmol) and 2,6-dichloro-1,3-benzothiazole (61.3 mg, 0.30 mmol) in asimilar manner to the method described for4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid, providing 17.2 mg (18%) of the desired product. ¹H NMR (400 MHz,DMSO-d₆) δ 12.10 (br s, 1H), 10.75 (br s, 1H), 7.75-8.05 (m, 9H), 7.60(d, 1H), 7.35 (m, 1H), 3.40 (q, 1H), 3.10 (m, 1H), 1.55 (m, 2H), 1.35(m, 2H), 0.85 (t, 3H). LC-MS m/z 479.3 (MH⁺), ret. time 3.88 min.

EXAMPLE 64-[4′-(1,3-Benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl-4-oxobutanoicacid

[0380]

[0381] To a solution of ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-2-(2-methoxyethyl)-4-oxobutanoate (75mg, 0.21 mmol) in butanol (4 mL), 2-chloro-benzothiazole (43 mg, 0.25mmol) was added and the reaction mixture was heated at 90° C. overnight.The solvent was removed by rotary evaporation, the residue wasredissolved in DMF (1 mL), a solution of 1 N aqueous NaOH (0.63 mL, 0.63mmol) was added, and the mixture was stirred at rt overnight. A solutionof 1 N aqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added tothe reaction mixture, and the crude product was purified by preparativereverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) toafford4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoicacid as a white solid (30 mg, 31%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.05 (d,2H), 7.95 (d, 2H), 7.70 (m, 5H), 7.60 (d, 1H), 7.30 (t, 1H), 7.15 (t,2H), 3.35 (m, 2H), 3.25 (s, 3H), 3.20 (m, 2H), 2.90 (m, 1H), 1.95-1.75(m, 2H); LC-MS ret. time 3.29 min (method 2), m/z 461.15 (MH⁺).

EXAMPLE 74-{4′-[(6Chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-[2-(dimethylamino)ethyl]-4-oxobutanoicacid

[0382]

[0383] This compound was prepared from methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2-[2-(dimethyl-amino)ethyl]4-oxobutanoate(60 mg, 0.17 mmol) and 2,6-dichloro-1,3-benzothiazole (51.8 mg, 0.25mmol) ) in a similar manner to the method described for4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid, providing 14.1 mg (13%) of the desired product as thetrifluoroacetate salt. ¹H NMR (400 MHz, CD₃OD) δ 8.10 (d, 2H), 7.70-8.10(m, 8H), 7.30 (m, 1H), 3.60 (m, 1H), 3.30-3.40 (m, 3H), 3.10 (m, 1H),2.95 (s, 6H), 2.20 (m, 1H), 2.00 (m, 1H). LC-MS m/z 508.1 (MH⁺), ret.time 2.66 min.

EXAMPLE 8(1R,2R)-2-({3′-Fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0384]

[0385] Butyl(1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate

[0386] Step 1. Methyl(1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclo-pentanecarboxylate(462 mg, 1.35 mmol) was dissolved in n-butanol (15 mL), and6-methoxy-2-(methylsulfonyl)-1,3-benzothiazole (162 mg, 0.8 mmol) and 4M aqueous HCl (1.5 mL) were added. The mixture was heated at 90° C. for5 h. An additional portion of6-methoxy-2-(methylsulfonyl)-1,3-benzothiazole (162 mg, 0.8 mmol) wasadded, and the mixture was stirred overnight at 90° C. Solvent was thenremoved by rotary evaporation, and the residue was purified by flashchromatography (Biotage Flash 40 M, 3:1 hexane/EtOAc) to afford butyl(1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate(480 mg, 65%). LC-MS ret. time 4.36 min, m/z 547.3 (MH⁺); ¹H NMR (300MHz, CDCl₃) δ 0.85 (t, 3H), 1.25-1.35 (m, 2H), 1.40-1.58 (m, 2H),1.74-1.84 (m, 3H), 1.91-1.96 (m, 1H), 2.11-2.20 (m, 2H), 3.40-3.46 (m,1H), 3.84 (s, 3H), 4.03 (t, 2H), 6.81-6.87 (m, 1H), 6.98 (dd, 1H), 7.18(d, 1H), 7.40-7.52 (m, 2H), 7.64 (d, 2H), 8.14 (d, 2H), 8.42 (t, 1H).

[0387](1R,2R)-2-({3′-Fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-yl}-carbonyl)cyclopentanecarboxylicacid

[0388] Step 2. To a solution of butyl(1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)-amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylatein methanol (8 mL) was added 1 N aqueous sodium hydroxide (6.15 mL), andthe mixture was stirred at 50° C. overnight. The solvent was thenremoved by rotary evaporation. Water (5 mL) was added to the residue,and the mixture was extracted with ethyl acetate. The aqueous layer wasthen treated with 1 N aqueous HCl to adjust the acidity to pH 2, andthen extracted with ethyl acetate. The organic phase was evaporatedunder reduced pressure, and the residue was purified by flashchromatography (Biotage Flash 40S, 6:1 EtOAc/hexane) to afford(1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid (129 mg, 30%, 89% ee). LC-MS ret. time 3.56 min, m/z 491.3 (MH⁺);¹H NMR (300 MHz, DMSO-d₆) δ 1.58-1.84 (m, 4H), 1.96-2.01 (m, 1H),2.14-2.17 (m, 1H). 3.22 (q, 1H), 3.77 (s, 3H), 4.02-4.10 (q, 1H), 6.94(dd, 1H), 7.46 (d, 1H), 7.53 (d, 1H), 7.65-7.76 (m, 2H), 7.86 (d, 2H),8.04 (d, 2H), 8.72 (t, 1H), 10.33 (br s, 1H).

EXAMPLE 92,2-Dimethyl-4-{4′-[(5-nitro-1,3-thiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoicacid

[0389]

[0390] In a 8-mL screw-cap vial, a mixture of4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg,0.20 mmol) and 2-bromo-5-nitro-1,3-thiazole (63.3 mg, 0.30 mmol) in 4 mLn-butanol was heated at 90° C. overnight. The solvent was removed underreduced pressure. The mixture was dissolved in 5 mL 1:4 MeOH/DMF andpurified by reverse-phase HPLC to provide 8.9 mg (10%) of the desiredproduct. ¹H NMR (400 MHz, DMSO-d₆) δ 11.55 (br s, 1H), 8.50 (s, 11H),7.70-8.05 (m, 8H), 3.15 (d, 1H), 1.25 (s, 6H); LC-MS m/z 426.2 (MH⁺),ret. time 3.12 min.

EXAMPLE 104-(4′-{[4-(4-Chlorophenyl)-1,3-thiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoicacid

[0391]

[0392] In a 8-mL screw-cap vial, a mixture of4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg,0.20 mmol) and 2-(4-chlorophenyl)-2-oxoethyl thiocyanate (64 mg, 0.30mmol) in 4 mL n-butanol was heated at 90° C. overnight. The solvent wasremoved under reduced pressure. The mixture was dissolved in 5 mL 1:4MeOH/DMF and purified by reverse-phase HPLC to provide 6.8 mg (7%) ofthe desired product. ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (br s, 1H), 10.50(s, 1H), 7.75-8.00 (m, 10H), 7.50 (m, 3H), 3.30 (m, 2H), 1.05 (s, 6H);LC-MS m/z 491.2 (MH⁺), ret. time 3.83 min.

EXAMPLE 114-[4′-(1,3-Benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]-4-oxo-2-(2-phenylethyl)butanoicacid

[0393]

[0394] A solution of ethyl4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (100mg, 0.25 mmol) and 2-chlorobenzoxazole (38.3 mg, 0.25 mmol) in toluene(1.0 mL) was heated at reflux for 16 h. Solvent was removed underreduced pressure, and the residue was dissolved in dichloromethane. Thesolution was washed with water, solvent was again removed under reducedpressure, and the residue was dissolved in methanol (1 mL) andtetrahydrofuran (1 mL). A 1 N aqueous solution of sodium hydroxide (0.77mL, 0.77 mmol) was added, and the mixture was stirred at rt for 16 h andthen concentrated under reduced pressure. The residue was purified bypreparative reverse-phase HPLC (water/acetonitrile gradient, containing0.1% TFA) to afford4-[4′-(1,3-benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]4-oxo-2-(2-phenylethyl)butanoicacid (40 mg, 33% yield). LC-MS ret. time 4.14 min, m/z 519.5 (MH⁺); ¹HNMR (300 MHz, DMSO-d₆) δ 1.82-1.90 (m, 2H), 2.68 (m, 2H), 2.80-2.85 (m,1H), 3.16 (dd, 1H), 3.41 (m, 1H), 7.10-7.30 (m, 8H), 7.48 (t, 2H),7.78-7.86 (m, 4H), 7.89 (d, 2), 8.02 (d, 2H), 10.83 (br s, 1H).

EXAMPLE 122,2-Dimethyl-4-{4′-[(6-methyl-1,3-benzoxazol-2yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoicacid

[0395]

[0396] To a solution of methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL),6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) wasadded, and the mixture was heated at 85° C. overnight. The solvent wasremoved by rotary evaporation, and the residue was redissolved in DMF (5mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, andthe mixture was heated at 65° C. overnight. A solution of 1 N aqueousHCl (0.24 mL, 0.24 mmol) and methanol (5 mL) were added to the reactionmixture and the crude product was purified by preparative reverse-phaseHPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford2,2-dimethyl4-{4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid as a white solid (32.6 mg, 32.1%). ¹H NMR (300 MHz, DMSO-d₆) δ8.00-7.50 (m, 8H), 7.30 (d, 2H), 7.05 (d, 1H), 3.30 (s, 2H), 2.50 (s,3H), 1.10 (s, 6H); LC-MS ret. time 3.53 min (method 2), m/z 429.17(MH⁺).

EXAMPLE 132,2-Dimethyl-4-{4′-[(4-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoicacid

[0397]

[0398] To a solution of methyl4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24mmol) in dichloroethane (3 mL),4-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) wasadded, and the mixture was heated at 85° C. overnight. The solvent wasremoved by rotary evaporation and the residue was redissolved in DMF (5mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, andthe mixture was heated at 65° C. overnight. A solution of 1 N aqueousHCl (0.24 mL, 0.24 mmol) and methanol (5 mL) was added to the reactionmixture and the crude product was purified by preparative reverse-phaseHPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford2,2-dimethyl-4-{4′-[(4-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid as a white solid (32.6 mg, 32.1%). ¹H NMR (300 MHz, DMSO-d₆) δ8.00-7.80 (m, 8H), 7.30 (d, 1H), 7.05 (d, 2H), 3.30 (s, 2H), 2.50 (s,3H), 1.10 (s, 6H); LC-MS ret. time 3.77 min (method 2), m/z 429.2 (MH⁺).

EXAMPLE 14trans-2-({4′-[(5-Fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0399]

[0400] To a solution of methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane carboxylate(100 mg, 0.31 mmol) in dichloroethane (3 mL),5-fluoro-2-(methylsulfonyl)-1,3-benzoxazole (80 mg, 0.37 mmol) was addedand the mixture was heated at 85° C. overnight. The solvent was removedby rotary evaporation, and the residue was redissolved in DMF (5 mL). Asolution of 1 N aqueous NaOH (0.93 mL, 0.93 mmol) was added and themixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl(0.31 mL, 0.31 mmol) and methanol (5 mL) were added to the reactionmixture, and the crude product was purified by preparative reverse-phaseHPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid as a white solid (43.7 mg, 31.4%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.05(d, 2H), 7.90-7.80 (m, 6H), 7.50 (m, 1H), 7.30 (m, 1H), 6.95 (m, 1H),4.05 (m, 1H), 3.20 (m, 1H), 2.20 (m, 1H), 1.95 (m, 1H), 1.80-1.60 (m,4H); LC-MS ret. time 3.66 min (method 2), m/z 445.1 (MH⁺).

EXAMPLE 15(1R,2R)-2-({3′-Fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0401]

[0402] To a solution of methyl(1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate(800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL),6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) wasadded, and the mixture was heated at 85° C. overnight. The solvent wasremoved by rotary evaporation, and the residue was purified by using aBiotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc)to give methyl(1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-(20mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, andthe mixture was heated at 50° C. overnight. The solvent was removed byrotary evaporation, and water (20 mL) and EtOAc (40 mL) were added tothe residue. The aqueous layer was separated, acidified to pH 5 by theaddition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL).The combined organic phases were washed with saturated NaCl and dried(Na₂SO₄). The solvent was removed by rotary evaporation and the residuewas redissolved in DMF (10 mL) and methanol (20 mL). The crude productwas purified by preparative reverse-phase HPLC (water/acetonitrilegradient, containing 0. 1% TFA) to afford(1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid as an off-white solid (161 mg, 15% yield, 80% ee). ¹H NMR (300 MHz,DMSO-d₆) δ 8.40 (m, 1H), 8.00-7.60 (m, 6H), 7.30 (d, 2H), 7.00 (d, 1H),4.05 (m, 1H), 3.20 (m, 1H), 2.40 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H),1.80-1.60 (m, 4H); LC-MS ret. time 3.57 min, m/z 459.3 (MH⁺).

EXAMPLE 16trans-2-({4′-[(5-Fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0403]

[0404] Methyltrans-2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-}carbonyl)-cyclopentanecarboxylate

[0405] Step 1. 2-Chloro-5-fluoro-1,3-benzothiazole (29 mg, 0.16 mmol)and methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate(50 mg, 0.16 mmol) were combined in 1-butanol. The solution was treatedwith 4 M HCl in dioxane (4 μL, 0.016 mmol) and heated at 90° C. for 18h. The reaction mixture was concentrated under reduced pressure. Theresidue was suspended in methanol, and the resulting solid was collectedby filtration and dried in vacuo. The title compound was obtained as apale yellow solid (55 mg, 77%); LC-MS m/z 475.3 (MH⁺), retention time3.97 minutes.

[0406]trans-2-({4′-[(5-Fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylicacid

[0407] Step 2. A solution of 1 N aqueous sodium hydroxide solution (1mL) was added to trans-methyl2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-methylhomogeneous, and the resulting solution was heated at 60° C. for 1 h.The reaction was concentrated under reduced pressure to remove excesssolvents, and the residue was partitioned between water andchloroform/isopropanol (4:1). The aqueous layer was adjusted to pH 2 byaddition of aqueous phosphoric acid solution, with stirring. The organiclayer was then separated, dried (Na₂SO₄), and concentrated under reducedpressure. The residue was suspended in acetone, and the resulting solidwas collected by filtration and dried in vacuo to provide the titlecompound (45 mg, 84%). ¹H NMR (300 MHz, acetone-d₆) δ 10.40-10.10 (br s,1H), 8.15 (d, 2H), 8.01 (d, 2H), 7.87-7.82 (m, 5H), 7.41 (dd, 1H),7.05-6.95 (m, 1H), 4.26-4.17 (m, 1H), 3.43-3.34 (m, 1H), 2.31-2.23 (m,1H), 1.98-1.70 (m, 5H); LC-MS m/z 461.3 (MH⁺), retention time 3.56minutes.

EXAMPLE 17(1R,2R)-2-[(4′-{[6-(Trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylicacid

[0408]

[0409] A mixture of methyl(1R,2R)-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate(150 mg, 0.464 mmol) and2-chloro-6-(trifluoromethyl)-1,3-benzothiazole(132 mg, 0.557 mmol) wasdiluted with n-butanol (3 mL) and treated with a catalytic amount of 4 MHCl in dioxane. The suspension was heated at 90° C. overnight. Thereaction mixture was concentrated under reduced pressure and purified byflash chromatography on silica gel, eluting with a gradient from 9:1 to3:2 hexanes/ethyl acetate. The product obtained was suspended in diethylether, and the resulting solid was collected by filtration and washedwith additional diethyl ether and hexanes. LC-MS for the n-butyl ester:LC-MS m/z 567.3 (MH⁺), 4.67 min; ¹H NMR (300 MHz, CDCl₃) δ 8.14-8.10 (m,3H), 7.80-7.71 (m, 6H), 7.62 (d, 2H), 4.17-4.13 (m, 1H), 4.09-4.04 (m,2H), 3.51-3.41 (m, 1H), 2.21-2.13 (m, 2H), 1.97-1.90 (m, 1H), 1.81-1.78(m, 3H), 1.58-1.51 (m, 2H), 1.35-1.28 (m, 2H),1.23-1.18 (t, 3H), 0.88(t, 2H). The off-white solid was diluted with methanol (2 mL) andtetrahydrofuran (2 mL) and treated with 2 M aqueous sodium hydroxidesolution (2 mL). The solution was stirred overnight at rt. The mixturewas acidified by the addition of an excess of 2 M aqueous hydrochloricacid solution. The acidic solution was extracted with ethyl acetate. Theorganic phases were combined, dried (MgSO₄), and concentrated underreduced pressure. The residue was suspended in methanol and theresulting solids were removed by filtration. The filtrate, whichcontained the product, was concentrated under reduced pressure toprovide the title compound as a pale orange solid (30 mg, 13% overallyield). ¹H NMR (tetrahydrofuran-d₈) δ 10.85 (s, 1H), 8.11-8.07 (m, 3H),7.96-7.91 (m, 2H), 7.79-7.71 (m, 5H), 7.63-7.59 (dd, 1H), 4.18 (q, 1H),3.37 (q, 1H), 2.2-1.77 (m, 6H); LC-MS m/z 511.3 (MH⁺), retention time4.27 minutes.

EXAMPLE 18(1R,2R)-2-({4′-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0410]

[0411] A suspension ofN-(4-iodo-2-fluorophenyl)-6-chloro-1,3-benzothiazol-2-amine (200 mg,0.49 mmol), bis(pinacolato)diboron (130 mg, 0.52 mmol), KOAc (150 mg,1.48 mmol), and PdCl₂(dppf) (30 mg, 0.04 mmol) in DMF (5.0 mL) wasdegassed by bubbling a flow of nitrogen for 30 minutes. The reactionmixture was heated under nitrogen at 85° C. for 3 h. After the mixturewas cooled to rt, (1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylic acid(140 mg, 0.49 mmol, >99% ee), Cs₂CO₃ (400 mg, 1.23 mmol) and PdCl₂(dppf)(30 mg, 0.04 mmol) were added, and the reaction mixture was heated at85° C. under nitrogen for 3 h. TLC analysis showed little startingmaterials remaining. The reaction mixture was cooled to rt, and dilutedwith water (50 mL). After the mixture was filtered through a pad ofCelite®, 1 N HCl was added to the filtrate to adjust the acidity topH<3. The solid that formed was collected by filtration, then dissolvedin EtOAc (50 mL), and the resulting solution was dried over Na₂SO₄.Removal of solvent and drying in vacuo provided the desired product (120mg, 60%, >99% ee). LC-MS m/z 495.3 (MH⁺), retention time 4.01 min.

EXAMPLE 19trans-2-({4′-[(6-Chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutanecarboxylicacid

[0412]

[0413] To a solution of methyl trans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutane-carboxylate (100 mg, 0.32 mmol) in n-butanol (15mL) was added 2,6-dichloro-1,3-benzothiazole (396 mg, 1.94 mmol), andthe resulting reaction mixture was heated at 90° C. overnight. Themixture was evaporated to dryness and the residue was brought up inMeOH. Then 1 N aqueous NaOH (1.0 mL, 1.0 mmol) was added to thesuspension, and the reaction mixture was stirred at 50° C. overnight.The reaction mixture was concentrated, and the residue was suspended inwater. Concentrated HCl was added to adjust the acidity to pH 1, and theprecipitate that formed was collected by filtration, washed with waterand MeOH, and dried in a vacuum oven to givetrans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutanecarboxylic acid (16 mg,10%). LC-MS ret. time 3.69; m/z 463.1 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ2.01-2.23 (m, 3H), 2.32 (m, 1H), 3.43 (m, 1H), 4.32 (m, 1H), 7.35 (m,1H), 7.31 (m, 1H), 7.62 (d, 1H), 7.81 (m, 4H), 7.90 (d, 2H), 7.98 (m,3H), 10.77 (s, 1H), 12.29 (s, 1H).

EXAMPLE 20trans-2-({4′-[(6-Methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0414]

[0415] N-(4-iodophenyl)-6-methyl-1,3-benzothiazol-2-amine (0.28 g, 0.78mmol) and methyltrans-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopentanecarboxylate(0.25 g, 0.71 mmol) were combined in a dry flask under argon. Toluene(15 mL), EtOH (6 mL), and saturated aqueous NaHCO₃ (2 mL) were thenadded, and the resulting solution was degassed by bubbling a flow ofargon for 30 minutes. Then[1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium (II), complexwith dichloromethane (1:1) (57 mg, 0.07 mmol) was added, and theresulting mixture was heated at 85° C. for 16 h. The reaction mixturewas then diluted with EtOAc and filtered through a Celite® pad. Thesolvent was removed by rotary evaporation and the residue was brought upin MeOH. Then 1 N aqueous NaOH (2.0 mL, 2.0 mmol) was added to thesuspension, and the reaction mixture was stirred at 50° C. overnight.The reaction mixture was concentrated under reduced pressure and theresidue was suspended in water. Concentrated HCl was added to adjust theacidity to pH 1, and the suspension was extracted with EtOAc. Thecombined organic phases were washed with brine, dried over sodiumsulfate, passed through a pad of silica gel, and concentrated in vacuo.The residue was brought up in EtOAc and the precipitate was collected byfiltration, washed with EtOAc, MeOH, and DCM, and dried in a vacuum ovento affordtrans-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-(400MHz, DMSO-d₆) δ 1.57-1.86 (m, 4H), 2.00 (m, 1H), 2.17 (m, 1H), 2.37 (s,3H), 3.22 (q, 1H), 4.08 (q, 1H), 7.14 (m, 1H), 7.51 (d, 1H), 7.61 (s,1H), 7.80 (m, 3H), 7.89 (d, 2H), 8.05 (d, 2H), 10.58 (s, 1H), 12.19 (s,1H).

EXAMPLE 21(1R,2R)-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0416]

[0417] Methyl(R,R)-trans-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate

[0418] Step1N-(4-bromo-2-fluorophenyl)-4-methyl-1,3-benzothiazol-2-amine (0.10 g,0.30 mmol) and methyl(R,R)-trans-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopentanecarboxylate (0.19 g, 0.54 mmol, 94% ee) werecombined in a dry flask under argon. Toluene (25 mL), EtOH (8 mL), andsaturated aqueous NaHCO₃ (5 mL) were added, and the resulting suspensionwas degassed by bubbling with a flow of argon for 30 minutes. Then[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (40 mg, 0.05 mmol) was added, and theresulting mixture was heated at 85° C. for 16 h. The reaction mixturewas then diluted with EtOAc and the layers were separated. The organiclayer was washed with aqueous HCl (1.0 M), water and brine, filtered,and concentrated in vacuo. The residue was purified by flashchromatography (Biotage Flash 25S) using 10 to 15% ethyl acetate inhexane to afford methyl(R,R)-trans-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate(0.09 g, 37%). ¹H NMR (400 MHz, CD₂Cl₂) δ 1.75-1.86 (m, 3H), 1.93 (m,1H), 2.12-2.26 (m, 2H), 2.69 (s, 3H), 3.45 (q, 1H), 3.66 (s, 3H), 4.12(q, 1H), 7.14 (t, 1H), 7.22 (d, 1H), 7.50 (m, 2H), 7.56 (t, 2H), 7.73(d, 2H), 8.07 (d, 2H), 8.72 (t, 1H).

[0419](R,R)-trans-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentanecarboxylicacid

[0420] Step 2 Methyl(R,R)-trans-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate(90 mg, 0.18 mmol) was brought up in MeOH. Then 1 N aqueous NaOH (1.0mL, 1.0 mmol) was added to the suspension, and the reaction mixture wasstirred at 50° C. overnight. The reaction mixture was concentrated, andthe residue was suspended in water. Conc. HCl was added to adjust theacidity to pH 1, and the mixture was extracted with EtOAc. The combinedorganic phases were washed with brine, dried over sodium sulfate,filtered and concentrated to give(R,R)-trans-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid (32 mg, 36%). LC-MS ret. time 3.97; m/z 475.3 (MH⁺); ¹H NMR (400MHz, DMSO-d₆) δ 1.56-1.83 (m, 4H), 2.00 (m, 1H), 2.16(m, 1H), 2.57 (s,3H), 3.22 (q, 1H), 4.09 (q, 1H), 7.07 (t, 1H), 7.16 (d, 1H), 7.63 (m,1H), 7.70 (m, 1H), 7.75 (m, 1H), 7.88 (d, 2H), 8.05 (d, 2H), 8.84 (t,1H), 10.47 (s, 1H).

EXAMPLE 22trans-2-({4′-[(4,6-Difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0421]

[0422] To a solution of racemic methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutane-carboxylate(250 mg, 0.77 mmol) in n-butanol (15 mL) was added2-chloro-4,6-difluoro-1,3-benzothiazole (318 mg, 1.55 mmol), and theresulting solution was heated at 90° C. overnight. The mixture was thenevaporated to dryness under reduced pressure, and the residue wasbrought up in MeOH. Then 1 N aqueous NaOH (8.0 mL, 8.0 mmol) was addedto the suspension, and the reaction mixture was stirred at 50° C.overnight. The reaction mixture was concentrated under reduced pressure,and the residue was suspended in water. Conc. HCl was added to adjustthe acidity to pH 1, and the mixture was extracted with EtOAc. Thecombined organic phases were washed with brine, dried over sodiumsulfate, filtered, and concentrated. The residue was brought up in MeOH,and the precipitate was collected by filtration, washed with MeOH,EtOAc, and DCM, and dried in a vacuum oven to afford racemictrans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1-biphenyl-4-yl}-carbonyl)cyclopentanecarboxylicacid (160 mg, 43%). LC-MS ret. time 4.12; m/z 479.3 (MH⁺); ¹H NMR (400MHz, DMSO-d₆) δ 1.55-1.86 (m, 4H), 2.00 (m, 1H), 2.18 (m, 1H), 3.22 (q,1H), 4.01 (q, 1H), 7.28 (m, 1H), 7.65 (m, 1H), 7.82 (m, 4H), 7.88 (d,2H), 8.05 (d, 2H), 10.83(s, 1H), 12.23 (s, 1H).

EXAMPLE 23(1R,2R)-2-({4′-[(4,6-Difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0423]

[0424] Racemictrans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentanecarboxylicacid (140 mg, 0.29 mmol) was separated by chiral HPLC to afford(1R,2R)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylicacid as the first-eluting enantiomer (13.2 mg, 9%, 99% ee). LC-MS ret.time 3.64; m/z 479.2 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 1.58-1.86 (m,4H), 2.00 (m, 1H), 2.17 (m, 1H), 3.21 (q, 1H), 4.10 (q, 1H), 7.29 (m,1H), 7.66 (m, 1H), 7.82 (m, 4H), 7.88 (d, 2H), 8.06 (d, 2H), 10.83 (s,1H), 12.23 (s, 1H).

EXAMPLE 24(1S,2S)-2-({4′-[(4,6-Difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0425]

[0426] Racemictrans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentanecarboxylicacid (140 mg, 0.29 mmol) was separated by chiral HPLC to afford(1S,2S)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylicacid as the second-eluting enantiomer (23.8 mg, 17%, 74% ee). LC-MS ret.time 3.65; m/z 479.2 (MH⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 1.56-1.87 (m,4H), 2.01 (m, 1H), 2.18 (m, 1H), 3.22 (q, 1H), 4.09 (q, 1H), 7.28 (m,1H), 7.66 (m, 1H), 7.82 (m, 4H), 7.89 (d, 2H), 8.06 (d, 2H), 10.83 (s,1H), 12.22 (s, 1H).

EXAMPLE 25(1R,2R)-2-({3′-fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0427]

[0428] Methyl(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate

[0429] Step 1. In a 100 mL 3-neck round bottom flask, a mixture ofmethyl (1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylate (3.11 g, 10mmol, 94.5% ee),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.54 g, 10mmol), and potassium acetate (2.94 g, 30 mmol) in 50 mLN,N-dimethylformamide was degassed by bubbling a flow of nitrogen gasfor 30 minutes. Palladium (II) acetate (0.07 g, 0.30 mmol) was added tothe reaction mixture, and the mixture was heated at 85° C. for 3 h. Thetransformation of methyl(1R,2R)-2-(4-bromobenzoyl)cyclopentanecarboxylate to methyl(1R,2R)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopentanecarboxylatewas confirmed by TLC analysis. The mixture was cooled to rt and pouredinto a separation funnel. Ethyl acetate (100 mL) and H₂O (100 mL) wereadded. The organic layer was washed with water (2×50 mL) and treatedwith Na₂SO₄ and activated charcoal. The mixture was filtered through apad of silica gel, and the filtrate was concentrated under reducedpressure to provide methyl(1R,2R)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]cyclopentanecarboxylateas an oil. This oil was transferred to a 250-mL 3-neck round-bottomflask. To the flask,N-(4-bromo-2-fluorophenyl)-N-(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amine(3.66 g, 9 mmol), 150 mL toluene, 60 mL ethanol, and 20 mL saturatedaqueous NaHCO₃ were added. The mixture was degassed by bubbling nitrogengas for 30 minutes.1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II)dichloromethane complex (0.82 g, 1.0 mmol) was added to the reactionmixture. The mixture was heated at 85° C. overnight. The workupprocedure was then carried out in a similar to that described above. Thefiltrate was concentrated under reduced pressure and the solid residuewas ultrasonicated in 100 mL acetonitrile for 30 minutes and filtered togive the desired compound as a white solid (2.59 g, 52%). LC-MS m/z559.3 (MH), ret. time 4.75 min.

[0430](1R,2R)-2-({3′-Fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylicacid

[0431] Step 2. In 250-mL round-bottom flask, methyl(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate(2.53 g, 4.53 mmol) was dissolved in 100 mL of 1:1 THF/dioxanecontaining 5.0 molar equivalents of 1 N aqueous NaOH. The mixture wasstirred at rt overnight. The mixture was concentrated under reducedpressure to a volume of about 20 mL. Ethyl acetate (100 mL), water (30mL), and 5.1 molar equivalents of 1 N aqueous HCl were added to themixture. The mixture was transferred to a separation funnel. The organiclayer was washed with water (1×50 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The solid was ultrasonicated in 30 mLacetonitrile and filtered to give the desired compound as a white solid(1.96 g, 80%, 94.5% ee). ¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (br s, 1H),10.60 (bs, 1H), 8.70 (t, 1H), 7.60-8.20 (m, 8H), 7.30 (d, 1H), 4.70 (q,1H), 3.20 (q, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.50-1.90 (m, 4H); LC-MSm/z 545.3 (MH⁺), ret. time 3.93 min.

EXAMPLE 26(1R,2R)-2-({3′-Fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0432]

[0433] tert-Butyl(1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylatewas prepared from tert-butyl(1R,2R)-2-(bromobenzoyl)-cyclopentanecarboxylate andN-(4-bromo-2-fluorophenyl)-N-(6-fluoro-1,3-benzothiazol-2-yl)amine in asimilar manner to that described above for methyl(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate.A solution of the tert-butyl ester (1.5 g, 2.81 mmol) in 2.0 mL TFA and10 mL CH₂Cl₂ was stirred at rt overnight. After the solvent was removedby rotary evaporation, 50 mL EtOAc and 50 mL water were added. Theorganic layer was separated, washed with 50 mL water, and then driedover Na₂SO₄. After the solvent was removed by rotary evaporation, 5 mLEtOAc was added to the residue, followed by 5 mL hexanes. Theprecipitate that formed was collected by filtration to afford thedesired product as a light yellow solid (1.0 g, 77%, 95.2% ee). ¹H NMR(400 MHz, DMSO-d₆) δ 12.20 (br s, 1H), 10.50 (bs, 1H), 8.70 (t, 1H),7.60-8.10 (m, 8H), 7.20 (t, 1H), 4.10 (m, 1H), 3.20 (m, 1H), 2.20 (m,1H), 2.00 (m, 1H), 1.50-1.90 (m, 4H); LC-MS m/z 479.3 (MH⁺), ret. time3.64 min.

EXAMPLE 27(1R,2R)-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0434]

[0435] This compound was prepared fromN-(4-bromophenyl)-N-(5-methyl-1,3-benzoxazol-2-yl)amine (0.50 g, 1.65mmol), methyl (1R,2R)-2-(4-bromobenzoyl) cyclopentanecarboxylate (0.57g, 1.83 mmol, 94.5% ee) in a similar manner to the method described for(1R,2R)-2-({3′-fluoro-4′-[(6-trifluoromethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid. Yield: 17%. ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H), 8.05 (d,2H), 7.75-7.90 (m, 6H), 7.35 (d, 1H), 7.25 (s, 1H), 6.95 (d, 1H), 4.05(q, 1H), 3.20 (s, 1H), 2.40 (s, 3H), 2.15 (m, 1H), 2.00 (m, 1H),1.55-1.80 (m, 4H). LC-MS m/z 441.3 (MH⁺), ret. time 3.48 min.

EXAMPLE 28trans-2-({4′-[(5,7-Difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0436]

[0437] To a solution of methyltrans-2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclobutanecarboxylate(80 mg, 0.25 mmol) in n-butanol (8 mL) was added2-chloro-5,7-difluoro-1,3-benzothiazole (102 mg, 0.49 mmol) and HCl (4.0M in dioxane, 0.2 mL). The resulting reaction mixture was heated at 90°C. overnight. The mixture was evaporated to dryness, and the residue wasbrought up in MeOH. Then 1 N aqueous NaOH (2.0 mL, 2.0 mmol) was added,and the reaction mixture was stirred at 50° C. overnight. The reactionmixture was concentrated and the residue was suspended in water. Conc.HCl was added to adjust the acidity to pH 1, and the suspension wasextracted with EtOAc. The combined organic phases were washed withbrine, dried over sodium sulfate, filtered, and concentrated. Theresidue was brought up in MeOH, and the precipitate was collected byfiltration and dried under vacuum oven to affordtrans-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid (65 mg, 58%). LC-MS ret. time 3.75; m/z 479.2 (MH⁺). ¹H NMR (400MHz, DMSO-d₆) δ 1.55-1.84 (m, 4H), 2.01 (m, 1H), 2.18 (m, 1H), 3.22 (q,1H), 4.09 (q, 1H), 7.15 (m, 1H), 7.40 (m, 1H), 7.83 (m, 4H), 7.87 (d,2H), 8.05 (d, 2H), 11.00 (s, 1H), 12.12 (s, 1H).

EXAMPLE 29(1R,2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclopentanecarboxylicacid

[0438]

[0439] Methyl (1R2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}-cyclopentanecarboxylate.

[0440] Step 1. Methyl(1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylate(100 mg, 0.29 mmol, 80% ee) and 2-chlorobenzimiazole (49 mg, 0.32 mmol)were combined in 1,4-dioxane (2 mL) and treated with one molarequivalent of 4 M HCl in dioxane (73 μL). The mixture was heated at 90°C. for 18 h, then cooled to rt and concentrated under reduced pressureto an orange oil. The residue was purified by flash chromatography onsilica gel, eluting with 2:1 hexanes/ethyl acetate followed by methanolto provide the title compound as a dark oil (0.12 g, 90%). ¹H NMR (300MHz, MeOD-d₄) δ 8.09 (d, 2H), 7.81 (d, 2H), 7.75-7.67 (m, 3H), 7.46-7.40(m, 2H), 7.32-7.28 (m, 2H), 4.17-4.09 (m, 1H), 3.26-3.23 (m, 1H),2.24-2.16 (m, 1H), 2.10-2.02 (m, 1H), 1.91-1.68 (m, 4H); LC-MS m/z 458.4(MH⁺), retention time 2.48 minutes; TLC R_(f) 0.28 (2:1 hexanes/ethylacetate).

[0441](1R,2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-yl]carbonyl}-cyclopentanecarboxylic acid.

[0442] Step 2. Methyl(1R,2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]-carbonyl}cyclopentanecarboxylate(100 mg, 0.22 mmol) was dissolved in methanol and treated with an excessof 1 N aqueous sodium hydroxide solution (2.19 mL, 2.19 mmol). Thesolution was stirred at rt for 1 h, and then was concentrated underreduced pressure. The residue was partitioned between water and ethylacetate, and the aqueous layer was adjusted to pH 2 by the addition of 1N aqueous HCl. The organic layer was separated, washed with brine, dried(MgSO₄), and concentrated under reduced pressure to provide an orangeoil. The oil was suspended in THF and stirred until a precipitateformed. The precipitate was collected by filtration and washed withadditional THF to provide the title compound as a yellow solid (30 mg,31%, 80% ee). ¹H NMR (300 MHz, DMSO-d₆) δ 13.12 (br s, 1H), 11.30 (br s,1H), 8.12 (d, 2H), 7.96-7.76 (m, 5H), 7.46-7.42 (m, 2H), 7.30-7.26 (m,2H), 4.15-4.07 (m, 1H), 3.27-3.19 (m, 1H), 2.21-2.12 (m, 1H), 2.05-1.96(m, 1H), 1.86-1.55 (m, 4H); LC-MS m/z 444.4 (MH⁺), retention time 2.79minutes.

EXAMPLE 30trans-2-({4′-[(6-Chloro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid

[0443]

[0444] To a solution of cis-methyl2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate (200 mg,0.59 mmol) in n-butanol (8 mL) was added 2,6-dichloro-1,3-benzothiazole(241 mg, 1.19 mmol), and the resulting reaction mixture was heated at90° C. overnight. The mixture was evaporated to dryness and the residuewas combined with MeOH. Then 1 N NaOH (6.0 mL, 6.0 mmol) was added tothe suspension, and the reaction mixture was stirred at 50° C.overnight. The reaction mixture was concentrated under reduced pressure,and the residue was suspended in water. Concentrated aqueous HCl wasadded to adjust the acidity to pH 1, and the precipitate was collectedby filtration, washed with water and MeOH, and dried in a vacuum oven togivetrans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexanecarboxylicacid (45 mg, 15%). LC-MS m/z 491.1 (MH⁺), ret. time 3.90 min; ¹H NMR(400 MHz, DMSO-d₆) δ 1.13 (m, 1H), 1.28˜1.51 (m, 3H), 1.78 (m, 1H), 1.93(m, 1H), 2.09 (m, 1H), 2.68 (m, 1H), 3.63 (m, 1H), 7.35 (m, 1H), 7.60(m, 1H), 7.80 (m, 4H), 7.90 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 10.75(s, 1H).

EXAMPLE 31trans-2-({4′-[(5-Methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid

[0445]

[0446]trans-2-(Trimethylsilyl)ethyl-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl-}-carbonyl)cyclohexanecarboxylate

[0447] Step 1. N-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine (76.70mg, 0.25 mmol) andtrans-2-(trimethylsilyl)ethyl-2-(4-bromobenzoyl)cyclohexanecarboxylate(105.45 mg, 0.23 mmol) were combined in a clean dry flask under argon.Toluene (25 mL), EtOH (8 mL), and saturated aqueous NaHCO3 (5 mL) wereadded, and the resulting solution was degassed by bubbling with argonfor 30 minutes. Then, [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), 1:1 complex with dichloromethane (18.78 mg, 0.02 mmol)was added, and the resulting mixture was heated at 90° C. for 16 h. Thereaction mixture was then diluted with EtOAc and passed through aCelite® pad, and the solvent was removed by rotary evaporation. Silicagel chromatography (Biotage cartridge), eluting with 25% EtOAc in hexanegavetrans-2-(trimethylsilyl)ethyl-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylate(64 mg, 50%). ¹H NMR (400 MHz, CD₂Cl₂) δ-0.013 (s, 9H), 0.88 (m, 2H),1.41 (m, 3H), 1.71-2.15 (m, 5H), 2.44 (s, 3H), 2.73 (m, 1H), 3.88 (m,1H), 4.08 (m, 2H), 7.08 (d, 1H), 7.21 (s, 1H), 7.33 (d, 1H), 7.67 (m,2H), 7.69 (m, 2H), 7.73 (m, 2H), 7.89 (m, 1H), 7.91 (m, 1H).

[0448]trans-2-({4′-[(5-Methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexane-carboxylicacid.

[0449] Step 2. To a solution oftrans-2-(trimethylsilyl)ethyl-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)-amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylate(64 mg, 0.12mmol) in THF (2 mL) was added tetrabutylammonium fluoride(1.0 M in THF, 0.70 mL), and then the reaction mixture was stirred at rtfor 16 h. Saturated aqueous NH₄Cl was added, and the reaction mixturewas diluted with EtOAc and water. The organic layer was separated andthe aqueous layer was extracted with EtOAc. The combined organic phaseswere washed with water and brine, dried over Na₂SO₄, filtered, andevaporated under reduced pressure. The residue was treated with MeOH,and the precipitate was collected by filtration and dried in a vacuumoven to givetrans-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylicacid (44.3 mg, 84%). LC-MS m/z 455.3 (MH⁺), ret. time 3.57 min. ¹H NMR(400 MHz, DMSO-d₆) δ 1.21 (m, 1H), 1.37 (m, 2H), 1.63 (m, 1H), 1.85 (m,3H), 2.05 (m, 1H), 2.38 (s, 3H), 2.69 (m, 1H), 3.95 (m, 1H), 7.03 (d,1H), 7.33 (d, 2H), 7.76 (m, 4H), 7.85 (d, 2H), 7.93 (d, 2H), 10.73 (s,1H).

EXAMPLE 32cis-3-[4′-(6-Chloro-benzothiazol-2-ylamino)-biphenyl-4-carbonyl]-cyclohexanecarboxylicacid

[0450]

[0451]cis-3-[4′-(6-Chloro-benzothiazol-2-ylamino)-biphenyl-4-carbonyl]-cyclohexanecarboxylicacid

[0452] To a solution of3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl ester(100 mg, 0.3 mmol) in butanol (5 mL), 2,6-dichloro-benzothiazole (60 mg,0.3 mmol) and 5 drops of 4 M HCl in dioxane were added, and the reactionmixture was heated at 90° C. for 5 h. An additional sample of2,6-dichlorobenzothiazole (60 mg, 0.3 mmol) and 5 drops of 4 M HCl indioxane were then added, and the reaction mixture was heated overnightat 90° C. The solvent was removed by rotary evaporation, the residue wasdissolved in DMF (2 mL), 1 N aqueous NaOH (0.3 mL, 0.3 mmol) was added,and the mixture was heated at 75° C. overnight. A solution of 1 Naqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to thereaction mixture, and the crude product was purified by preparativereverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) toaffordcis-3-[4′-(6-chloro-benzothiazol-2-ylamino)-biphenyl-4-carbonyl]-cyclohexanecarboxylicacid as a white solid (12.6 mg, yield 23.4%). ¹H NMR (300 MHz, DMSO) δ8.05 (d, 2H), 7.75-8.00 (m, 7H), 7.50 (d, 1H), 7.35 (d, 1H), 3.25 (m,1H), 2.50 (m, 1H), 2.20-1.90 (m, 4H), 1.70-1.50 (m, 4H); LC-MS ret. time3.99 min (method 2), m/z 491.11 (MH⁺).

EXAMPLE 33trans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid

[0453]

[0454] Methyl 2-[(4′-aminobiphenyl-4-yl)carbonyl]cyclopentanecarboxylate(264 mg, 0.02 mmol) was dissolved in n-butanol (8 mL),2-chloro-5,6-difluoro-1H-benzimidazole (185 mg, 0.98 mmol) and 4 N HCl(0.2 mL) were then added, and the resulting mixture was heated at 90° C.for 5 h. The mixture was then cooled to rt, and solvent was removedunder reduced pressure. The residue was dissolved in methanol (5 mL) andtetrahydrofuran (5 mL), and then treated with 1 N aqueous sodiumhydroxide (2.45 mL, 2.45 mmol). The mixture was stirred at rt for 16 hand then concentrated under reduced pressure. The residue was purifiedby preparative reverse-phase HPLC (water/acetonitrile gradient,containing 0.1% TFA) to affordtrans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid (9.1 mg, 3%). LC-MS m/z 462.3 (MH⁺), ret. time 3.23 min; ¹H NMR(300 MHz, DMSO-d₆) δ 1.69-1.81 (m, 4H), 1.98-2.18 (m, 2H), 3.14-3.22 (m,1H), 4.04-4.09 (m, 1H), 7.38 (t, 2H), 7.77-7.84 (m, 6H), 8.05 (d, 2H).

Preparation of Compounds of Formula (Ia) EXAMPLE 34(1R,2R)-2-[{3-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}(hydroxy)methyl]cyclopentanecarboxylicacid

[0455]

[0456] To a solution of(1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclopentanecarboxylicacid (300 mg, 0.63 mmol) in THF (6 mL), a solution of sodium borohydride(23.82 mg, 0.63 mmol) in water (3 mL) was added. The reaction mixturewas stirred at rt for 3 hours. The solvent was removed, the residue wasthen dissolved in methanol (2 mL), and the desired product was isolatedby preparative reverse-phase HPLC (water/acetonitrile gradient,containing 0.1% TFA). Two diastereomers of(1R,2R)-2-[{3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}(hydroxy)methyl]cyclopentanecarboxylicacid were obtained: a more polar isomer (15 mg, yield 5%). LC-MS m/z481.3 (MH⁺), ret. time 3.33 min; ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (t,1H), 7.60 (d, 1H), 7.50 (m, 5H), 7.35 (d, 2H), 7.15 (t, 1H), 4.60 (d,1H), 2.65 (m, 1H), 2.45 (m, 1H), 1.85 (m, 1H), 1.70-1.40 (m, 5H); and aless polar isomer (10 mg, yield 3%); LC-MS m/z 481.3 (MH⁺), ret. time3.46 min; ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (t, 1H), 7.60 (d, 1H), 7.50(m, 5H), 7.35 (d, 2H), 7.15 (t, 1H), 4.60 (d, 1H), 2.65 (m, 1H), 2.45(m, 1H), 1.85 (m, 1H), 1.65 (m, 1H), 1.50 (m, 3H), 1.25 (m, 1H).

Preparation of Compounds of Formula (Ib)

[0457] It will be recognized by those skilled in the art that compoundsof Formula (Ia) can be converted to and isolated as the correspondingcyclic ester (lactone) having Formula (Ib), for example by spontaneousdehydration of the compound of Formula (Ia), or by dehydration of thecompound of Formula (Ib) induced by methods known in the art. Forexample, such methods for the formation of compounds of Formula (Ib)from compounds of Formula (Ia) include heating under dry conditions suchas in a vacuum oven; treatment with a catalytic amount of acid such asacetic acid, 4-toluenesulfonic acid, or trifluoroacetic acid in asuitable solvent such as acetonitrile, methylene chloride, or toluene;and treatment with a dehydrating reagent such asdicyclohexylcarbodiimide in the presence of 4-dimethylaminopyridine in asuitable solvent such as acetonitrile, methylene chloride, or toluene.

[0458] Using appropriate starting materials and the experimentalprocedures described above, compounds of Formula (I) were prepared aslisted in Table 1. Additional compounds of Formula (Ia) can be preparedby using appropriate starting materials and experimental proceduressimilar to that described above for(1R,2R)-2-[{3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}(hydroxy)methyl]cyclopentanecarboxylicacid. Compounds of Formula (Ib) can be prepared by using appropriatecompounds of Formula (Ia) as starting materials and applying methodssuch as described above. Additional compounds of Formula (I), Formula(Ia), and Formula (Ib) such as the compounds listed in Table 2, can beprepared by the methods described herein. It will be understood by thoseskilled in the art that some minor modifications to the describedprocedures may have been made, but such modifications do notsignificantly affect the results of the preparation. LC-MScharacterization of compounds, as listed in the table, was carried outby using the instrumentation and methods set forth above.

[0459] By using the above described methods and by substituting theappropriate starting material(s), other compounds of the invention weremade and characterized. These compounds, together with Examples 1-34,are summarized in Table 1 below. TABLE 1 Example LC-MS LC-MS No. Entrym/z ret. time LC-MS synthetic chirality & described No. Structure IUPACname (MH+) min method route route % ee in text 1

4-[4′-(1H-benzimidazol-2- ylamino)-1,1′-biphenyl-4-yl]2,2-dimethyl-4-oxobutanoic acid 414.3 2.27 1 B not chiral 2 2

4-{4′-[(5-methoxy-1H- benzimidazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 444.4 2.37 1 B not chiral 3

2-{[4′-(1H-benzimidazol-2- ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane- carboxylic acid 426.4 2.82 1 B trans racemicmixture 4

2-({4′-[(5-methoxy-1H- benzimidazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 456.3 2.31 1 B trans racemicmixture 5

2-[(4′-{[5-(trifluoromethyl)- 1H-benzimidazol-2-yl]amino}-1,1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid494.3 2.56 1 A trans racemic mixture 6

2-({4′-[(5,6-difluoro-1H- benzimidazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 462.3 3.23 1 B trans racemicmixture 33 7

(1R, 2R)-2-{[4′-(1H- benzimidazol-2-ylamino)-3′- fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclopentane- carboxylic acid 444.4 2.80 1 B R, R-trans(from chiral inter- mediate) 80 29 8

(1R, 2R)-2-({3′-fluoro-4′-[(5- methoxy-1H-benzimidazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid474.3 2.29 1 B R, R-trans (from chiral inter- mediate) 74 9

(1R, 2R)-2-[(3′-fluoro-4′-{[5- (trifluoromethyl)-1H-benzimidazol-2-yl]amino}- 1,1′-biphenyl-4- yl)carbonyl]cyclopentane-carboxylic acid 512.3 2.69 1 A R, R-trans (from chiral inter- mediate)78 10

4-[4′-(1,3-benzoxazol-2- ylamino)-1,1′-biphenyl-4-yl]- 4-oxo-2-(2-phenylethyl)butanoic acid 491.2 3.68 1 B racemic mixture 11 11

2,2-dimethyl-4-{4′-[(6- methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}-4-oxobutanoic acid 429.2 3.51 2 B notchiral 12 12

4-{4′-[(6-chloro-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid 449.1 3.99 2 B not chiral 13

4-{4′-[(6-methoxy-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 445.2 3.47 2 B not chiral 14

2,2-dimethyl-4-{4′-[(5- methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}-4-oxobutanoic acid 429.2 3.77 2 B notchiral 15

2,2-dimethyl-4-{4′-[(4- methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}-4-oxobutanoic acid 433.2 3.80 2 B notchiral 13 16

2,2-dimethyl-4-oxo-4-[4′- (5,6,7,8- tetrahydronaphtho[2,3-d][1,3]oxazol-2-ylamino)- 1,1′-biphenyl-4-yl]butanoic acid 469.2 3.99 2B not chiral 17

4-{4′-[(5-fluoro-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 433.2 3.80 2 B not chiral 18

4-{4′-[(5-isopropyl-1,3- benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2- dimethyl-4-oxobutanoic acid 457.2 3.88 2 B notchiral 19

2,2-dimethyl-4-oxo-4-{4′- [(5-propyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}butanoic acid 457.2 3.95 2 B not chiral20

2-({4′-[(6-chloro-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 461.1 3.84 2 B trans racemicmixture 21

2-({4′-[(6-methoxy-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 457.2 3.55 2 B trans racemicmixture 22

2-({4′-[(5-fluoro-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 445.2 3.66 2 B trans racemicmixture 14 23

2-({4′-[(5,6-dimethyl-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 455.4 3.58 1 B trans racemicmixture 14 24

2-{[4′-(1,3-benzoxazol-2- ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane- carboxylic acid 427.3 3.31 1 B trans racemicmixture 25

2-({4′-[(6-methyl-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 441.2 3.88 2 B trans racemicmixture 26

2-({4′-[(5-methyl-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 441.2 3.84 2 B trans racemicmixture 27

(1R, 2R)-2-({4′-[(5-fluoro- 1,3-benzoxazol-2- yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 445.3 3.41 1 B R, R-trans(from chiral inter- mediate) 94 28

(1R, 2R)-2-({4′-[(6-chloro- 1,3-benzoxazol-2- yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 461.4 3.67 1 B R, R-trans(from chiral inter- mediate) 97 29

(1R, 2R)-2-({4′-[(6-methyl- 1,3-benzoxazol-2- yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 441.3 3.47 1 B R, R-trans(from chiral inter- mediate) 80 30

(1R, 2R)-2-({4′-[(5-methyl- 1,3-benzoxazol-2- yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 441.3 3.48 1 A R, R-trans(from chiral prep- HPLC) 96 27 31

(1R, 2R)-2-[(4′-{[5- (trifluoromethyl)-1,3- benzoxazol-2-yl]amino}-1-1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid 495.3 4.15 1A R, R-trans (from chiral inter- mediate) 98 32

(1R, 2R)-2-({4′-[(6-fluoro- 1,3-benzoxazol-2- yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 445.2 3.39 1 B R, R-trans(from chiral prep- HPLC) >99 33

(1S, 2S)-2-({4′-[(6-fluoro- 1,3-benzoxazol-2- yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 445.2 3.39 1 B S, S-trans(from chiral prep- HPLC) >99 34

2-({4′-[(6-methyl-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclohexane- carboxylic acid 455.3 3.57 1 A trans- racemicmixture 35

2-({4′-[(5-methyl-1,3- benzoxazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclohexane- carboxylic acid 455.3 3.57 1 A trans- racemicmixture 31 36

4-{4′-[(5-methyl-1,3- benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxo-2- (2-phenylethyl)butanoic acid 505.3 3.74 1 Aracemic mixture 37

2-({3′-fluoro-4′-[(6-methoxy 1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid475.2 3.29 2 B trans racemic mixture 38

2-({4′-[(6-chloro-1,3- benzoxazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid 479.13.77 2 B trans racemic mixture 39

(1R, 2R)-2-({3′-fluoro-4′-[(6- fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid463.3 3.44 1 B R, R-trans (from chiral prep- HPLC) 80 40

(1R, 2R)-2-{(3′-fluoro-4′-[(5- fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid463.3 3.42 1 B R, R-trans (from chiral prep- HPLC) 82 41

(1R, 2R)-2-({3′-fluoro-4′-[(6- methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid459.3 3.57 1 B R, R-trans (from chiral inter- mediate) 80 15 42

(1R, 2R)-2-({3′-fluoro-4′-[(5- methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid459.3 3.54 1 A R, R-trans (from chiral inter- mediate) 94 43

(1R, 2R)-2-[(3′-fluoro-4′-{[5- (trifluoromethyl)-1,3-benzoxazol-2-yl]amino}- 1,1′-biphenyl-4- yl)carbonyl]cyclopentane-carboxylic acid 513.3 4.53 1 A R, R-trans (from chiral inter- mediate)96 44

4-[4′-(1,3-benzothiazol-2- ylamino)-1,1′-biphenyl-4-yl]- 2,2-dimethyl-4-oxobutanoic acid 431.2 3.40 1 B not chiral 1 45

4-{4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 465.2 3.76 1 B not chiral 46

4-{4′-[(6-methoxy-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2- dimethyl-4-oxobutanoic acid 461.2 3.40 1 B notchiral 47

2,2-dimethyl-4-oxo-4-[4′- (1,3-thiazol-2-ylamino)-1,1′-biphenyl-4-yl]butanoic acid 381.4 2.53 1 B not chiral 3 48

4-[4′-(1,3-benzothiazol-2- ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4- oxobutanoic acid 461.2 3.29 2 B racemic mixture 649

4-{4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-(2- methoxyethyl)-4- oxobutanoic acid 495.1 3.66 2B racemic mixture 50

4-{4′-[(6-methoxy-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-(2- methoxyethyl)-4- oxobutanoic acid 491.2 3.25 2B racemic mixture 51

2-({4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclobutane- carboxylic acid 463.1 3.69 1 B trans racemicmixture 19 52

2-({4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 477.4 3.81 1 B trans racemicmixture 53

4-{4′-[(5-methoxy-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2- dimethyl-4-oxobutanoic acid 461.4 3.33 1 B notchiral 54

2,2-dimethyl-4-{4′-[(6-nitro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}-4-oxobutanoic acid 476.2 3.49 1 B notchiral 55

4-{4′-[(4-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 465.4 3.62 1 B not chiral 56

(1R, 2R)-2-{[4′-(1,3- benzothiazol-2-ylamino)- 1,1′-biphenyl-4-yl]carbonyl}cyclopentane- carboxylic acid 443.3 3.43 1 B R, R-trans(from chiral inter- mediate 97 57

2-{[4′-(1,3-benzothiazol-2- ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane- carboxylic acid 443.4 3.48 1 B trans racemicmixture 58

4-{4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxo-2- (2-phenylethyl)butanoic acid 541.3 4.07 1 Bracemic mixture 4 59

2-(2-{4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2- oxoethyl)pentanoic acid 479.3 3.88 1 B racemicmixture 5 60

2-({4′-[(5-methoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 473.3 3.42 1 B trans racemicmixture 61

2-({4′-[(6-nitro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 488.2 3.59 1 B trans racemicmixture 62

2-({4′-[(4-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 477.3 3.72 1 B trans racemicmixture 63

4-{4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-[2- (dimethylamino)ethyl]-4- oxobutanoic acid(trifluoroacetate salt) 508.1 2.66 1 B racemic mixture 7 64

2-[2-(dimethylamino)ethyl]- 4-{4′-[(5-methoxy-1,3-benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-4- oxobutanoic acid(trifluoroacetate salt) 504.2 2.42 1 B racemic mixture 65

2-[2-(dimethylamino)ethyl]- 4-{4′-[(6-nitro-1,3-benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-4- oxobutanoic acid(trifluoroacetate salt) 519.2 2.52 1 B racemic mixture 66

2-({4′-[(6-methoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 473.3 3.41 1 B trans racemicmixture 67

2-({4′-[(6-methyl-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 457.3 3.57 1 A trans racemicmixture 20 68

2-({4′-[(6-ethoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 487.4 3.64 1 B trans racemicmixture 69

2-({4′-[(6-fluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 461.4 3.63 1 B trans racemicmixture 70

(1R, 2R)-2-({4′-[(6-chloro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid477.4 3.85 1 B R, R-trans (from chiral prep- HPLC) 99 71

(1S, 2S)-2-({4′-[(6-chloro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid477.4 3.85 1 B S, S-trans (from chiral prep- HPLC) 92 72

2,2-dimethyl-4-{4′-[(5-nitro- 1,3-thiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4- oxobutanoic acid 426.2 3.14 1 B not chiral 9 73

4-(4′-{[4-(4-chlorophenyl)- 1,3-thiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-2,2-dimethyl- 4-oxobutanoic acid 491.2 3.83 1 B notchiral 10 74

(1R, 2R)-2-({4′-[(4,6- difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid479.2 3.64 1 B R, R-trans (from chiral prep- HPLC) 99 23 75

(1S, 2S)-2-({4′-[(4,6-difluoro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid479.2 3.65 1 B S, S-trans (from chiral prep- HPLC) 74 24 76

3-({4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclohexane- carboxylic acid 491.1 3.99 2 B cis racemicmixture 32 77

3-({4′-[(6-methoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclohexane- carboxylic acid 487.2 3.11 2 B cis racemicmixture 78

2-[(4′-{(6-(trifluoromethoxy)- 1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid527.3 3.87 1 B trans racemic mixture 79

(1R, 2R)-2-({4′-[(6-fluoro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid461.1 3.63 1 B R, R-trans (from chiral prep- HPLC) 99 80

(1R, 2R)-2-({4′-[(6-methyl- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid457.4 3.57 1 B R, R-trans (from chiral prep- HPLC) 99 81

(1S, 2S)-2-({4′-[(6-fluoro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid461.3 3.55 1 B S, S-trans (from chiral prep- HPLC) 99 82

(1S, 2S)-2-({4′-[(6-methyl- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid457.4 3.57 1 B S, S-trans (from chiral prep- HPLC) 99 83

2-({4′-[(4,6-difluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 479.3 4.12 1 B trans racemicmixture 22 84

2-({4′-[(4-methyl-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 457.3 3.71 1 B trans racemicmixture 85

2-({4′-[(5-fluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 461.3 3.56 1 B trans racemicmixture 16 86

2-[(4′-{[6-(trifluoromethyl)- 1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid511.3 4.27 1 B trans racemic mixture 17 87

2-({4′-[(5-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 477.2 3.78 1 B trans racemicmixture 88

2-({4′-[(5,7-dimethyl-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 471.3 3.70 1 B trans racemicmixture 89

2-[(4′-{[6-(methylsulfonyl)- 1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid521.2 3.60 1 B trans racemic mixture 90

2-({4′-[(5,6-dimethyl-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 471.3 3.65 1 B trans racemicmixture 91

4-{4′-[(6-ethoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 475.2 3.47 1 B nor chiral 92

4-{4′-[(6-fluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoic acid 449.2 3.46 1 B not chiral 93

2-({4′-[(5,7-difluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopentane- carboxylic acid 479.2 3.75 1 B trans racemicmixture 28 94

2-({4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopropane- carboxylic acid 449.2 3.70 1 B trans racemicmixture 95

(1R, 2R)-2-[(4′-{[5- (trifluoromethyl)-1,3- benzothiazol-2-yl]amino}-1,1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid 511.1 3.82 1A R, R-trans (from chiral inter- mediate) 90 96

2-{[4′-(1,3-benzothiazol-2- ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopropane- carboxylic acid 415.2 3.21 1 B trans racemicmixture 97

2-({4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclohexane- carboxylic acid 491.2 3.90 1 B trans racemicmixture 98

2-({4′-[(4-methyl-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopropane- carboxylic acid 429.2 3.49 1 B trans racemicmixture 99

2-({4′-[(6-methoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopropane- carboxylic acid 445.2 3.17 1 B trans racemicmixture 100

2-({4′-[(5,7-difluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopropane- carboxylic acid 451.1 3.53 1 B trans racemicmixture 101

2-({4′-[(4,6-difluoro-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclopropane- carboxylic acid 451.1 3.41 1 B trans racemicmixture 102

2-{[4′-(1,3-benzothiazol-2- ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclobutane- carboxylic acid 429.2 3.27 1 B trans racemicmixture 103

2-({4′-[(6-methoxy-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclobutane- carboxylic acid 459.2 3.42 1 B trans racemicmixture 104

2-({4′-[(4-methyl-1,3- benzothiazol-2-yl)amino]- 1,1′-biphenyl-4-yl}carbonyl)cyclobutane- carboxylic acid 443.2 3.73 1 B trans racemicmixture 105

(1R, 2R)-2-({4′-[(6-isopropyl- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid485.3 4.31 1 A R, R-trans (from chiral inter- mediate) 90 106

2-({4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid 495.13.91 2 B trans racemic mixture 107

2-({3′-fluoro-4′-[(6-methoxy- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid491.1 3.77 2 B trans racemic mixture 108

(1R, 2R)-2-({4′-[(6-chloro- 1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′- biphenyl-4- yl}carbonyl)cyclopentane-carboxylic acid 495.3 4.01 1 A R, R-trans (from chiral inter-mediate) >99 18 109

(1R, 2R)-2-({3′-fluoro-4′-[(6- methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid491.3 3.56 1 B R, R-trans (from chiral inter- mediate) 89 8 110

2-{[4′-(1,3-benzothiazol-2- ylamino)-3′-fluoro-1,1′- biphenyl-4-yl]carbonyl}cyclopentane- carboxylic acid 461.4 3.60 1 B trans racemicmixture 111

(1R, 2R)-2-({4′-[(4,6- difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′- biphenyl-4- yl}carbonyl)cyclopentane-carboxylic acid 497.2 3.71 1 B R, R-trans (from chiral prep- HPLC) >99112

(1S, 2S)-2-({4′-[(4,6-difluoro- 1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′- biphenyl-4- yl}carbonyl)cyclopentane-carboxylic acid 497.2 3.71 1 B S, S-trans (from chiral prep- HPLC) 95113

(1R, 2R)-2-[(3′-fluoro-4′-{[6- (trifluoromethyl)-1,3-benzothiazol-2-yl]amino}- 1,1′-biphenyl-4- yl)carbonyl]cyclopentane-carboxylic acid 529.3 4.33 1 B R, R-trans (from chiral inter- mediate)97 114

(1R, 2R)-2-({3′-fluoro-4′-[(5- fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid479.3 4.10 1 B R, R-trans (from chiral inter- mediate) 90 115

(1R, 2R)-2-({3′-fluoro-4′-[(4- methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid475.3 3.97 1 A R, R-trans (from chiral inter- mediate) 83 21 116

(1R, 2R)-2-({4′-(5-chloro- 1,3-benzothiazol-2- yl)amino]-3′-fluoro-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid 495.2 3.85 1 B R,R-trans (from chiral inter- mediate) 96 117

(1R, 2R)-2-({3′-fluoro-4′-[(6- fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid479.3 3.64 1 A R, R-trans (from chiral inter- mediate) 96 26 118

(1R, 2R)-2-({3′-fluoro-4′-[(6- methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid475.3 3.71 1 B R, R-trans (from chiral prep- HPLC) 90 119

(1R, 2R)-2-({4′-[(5,7- dimethyl-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′- biphenyl-4- yl}carbonyl)cyclopentane-carboxylic acid 489.3 3.85 1 A R, R-trans (from chiral inter- mediate)66 120

(1R, 2R)-2-({4′-[(5,7- difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′- biphenyl-4- yl}carbonyl)cyclopentane-carboxylac acid 497.2 3.84 1 A R, R-trans (from chiral inter- mediate)80 121

(1R, 2R)-2-[(3′-fluoro-4′-{[5- (trifluoromethyl)-1,3-benzothiazol-2-yl]amino}- 1,1′-biphenyl-4- yl)carbonyl]cyclopentane-carboxylic acid 529.1 3.90 1 A R, R-trans (from chiral inter- mediate)90 122

(1R, 2R)-2-[(3′-fluoro-4′-{(6- (trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}- 1,1′-biphenyl-4- yl)carbonyl]cyclopentane-carboxylic acid 545.3 3.93 1 A R, R-trans (from chiral inter- mediate)95 25 123

2-({3′-fluoro-4′-[(6-methoxy- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclobutane- carboxylic acid477.2 3.54 1 A trans racemic mixture 124

2-{[4′-(1,3-benzothiazol-2- ylamino)-3′-fluoro-1,1′- biphenyl-4-yl]carbonyl}cyclobutane- carboxylic acid 447.1 3.56 1 A trans racemicmixture 125

2-{[4′-(1,3-benzothiazol-2- ylamino)-3′-fluoro-1,1′- biphenyl-4-yl]carbonyl}cyclopropane- carboxylic acid 433.2 3.31 1 A trans racemicmixture 126

2-({3′-fluoro-4′-[(6-methoxy- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopropane- carboxylic acid463.2 3.47 1 A trans racemic mixture 127

(1R, 2R)-2-({3′-fluoro-4′-[(6- isopropyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid503.3 4.46 1 A R, R-trans (from chiral inter- mediate) 90 128

2-({3′-fluoro-4′-[(6-fluoro- 1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4- yl}carbonyl)cyclopentane- carboxylic acid479.3 3.65 1 B trans racemic mixture 129

2-[(3′-fluoro-4-{[6- (trifluoromethyl)-1,3- benzothiazol-2-yl]amino}-1,1′-biphenyl-4- yl)carbonyl]cyclopentane- carboxylic acid 529.3 3.89 1A trans racemic mixture 130

4-{4′-[(6-chloro-1,3- benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}-4- oxo-2-(2- phenylethyl)butanoic acid 559.24.13 1 A racemic mixture 131

(1R, 2R)-2-[{3′-fluoro-4′-[(6- fluoro-1,3-benzothiazol-2-yl)amino]-biphenyl-4- yl}(hydroxy)-methyl]- cyclopentane-carboxylic acid481.3 two isomers: 3.33 & 3.46 1 N/A R, R-trans cyclo- pentyl (fromchiral inter- mediate) 34

[0460] By using the methods described above and by selecting theappropriate starting materials, other compounds of the invention can bemade and are illustrated in Table 2 below. TABLE 2 Entry No. Structure132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

Methods of Use

[0461] As used herein, various terms are defined below.

[0462] When introducing elements of the present invention or thepreferred embodiment(s) thereof, the articles “a,” “an,” “the,” and“said” are intended to mean that there are one or more of the elements.The terms “comprising,” “including,” and “having” are intended to beinclusive and mean that there may be additional elements other than thelisted elements.

[0463] The term “subject” as used herein includes mammals (e.g., humansand animals).

[0464] The term “treatment” includes any process, action, application,therapy, or the like, wherein a subject, including a human being, isprovided medical aid with the object of improving the subject'scondition, directly or indirectly, or slowing the progression of acondition or disorder in the subject.

[0465] The term “combination therapy” or “co-therapy” means theadministration of two or more therapeutic agents to treat an obesecondition and/or disorder. Such administration encompassesco-administration of two or more therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each inhibitoragent. In addition, such administration encompasses use of each type oftherapeutic agent in a sequential manner.

[0466] The phrase “therapeutically effective” means the amount of eachagent administered that will achieve the goal of improvement in an obesecondition or disorder severity, while avoiding or minimizing adverseside effects associated with the given therapeutic treatment.

[0467] The term “pharmaceutically acceptable” means that the subjectitem is appropriate for use in a pharmaceutical product.

[0468] The compounds of Formula (I),Formula (Ia), and Formula (Ib) ofthis invention are expected to be valuable as therapeutic agents.Accordingly, an embodiment of this invention includes a method oftreating the various conditions in a patient (including mammals) whichcomprises administering to said patient a composition containing anamount of the compound of Formula (I), Formula (Ia), or Formula (Ib)that is effective in treating the target condition.

[0469] An object of this invention is to provide methods for treatingobesity and inducing weight loss in an individual by administration of acompound of the invention. The method of the invention comprisesadministering to an individual a therapeutically effective amount of atleast one compound of the invention, or a prodrug thereof, which issufficient to induce weight loss. The invention further comprises amethod of preventing weight gain in an individual by administering anamount of at least one compound of the invention, or a prodrug thereof,which is sufficient to prevent weight gain.

[0470] The present invention also relates to the use of the compounds ofthis invention for the treatment of obesity-related diseases includingassociated dyslipidemia and other obesity- and overweight-relatedcomplications such as, for example, cholesterol gallstones, gallbladderdisease, gout, cancer (e.g., colon, rectum, prostate, breast, ovary,endometrium, cervix, gallbladder, and bile duct), menstrualabnormalities, infertility, polycystic ovaries, osteoarthritis, andsleep apnea, as well as for a number of other pharmaceutical usesassociated therewith, such as the regulation of appetite and foodintake, dyslipidemia, hypertriglyceridemia, Syndrome X, type 2 diabetes(non-insulin-dependent diabetes), atherosclerotic diseases such as heartfailure, hyperlipidemia, hypercholesteremia, low HDL levels,hypertension, cardiovascular disease (including atherosclerosis,coronary heart disease, coronary artery disease, and hypertension),cerebrovascular disease such as stroke, and peripheral vessel disease.The compounds of this invention may also be useful for treatingphysiological disorders related to, for example, regulation of insulinsensitivity, inflammatory response, plasma triglycerides, HDL, LDL andcholesterol levels and the like.

[0471] Compounds of Formula (I), Formula (Ia), or Formula (Ib) may beadministered alone or in combination with one or more additionaltherapeutic agents. Combination therapy includes administration of asingle pharmaceutical dosage formulation which contains a compound ofFormula (I), Formula (Ia), or Formula (Ib) and one or more additionaltherapeutic agents, as well as administration of the compound of Formula(I), Formula (Ia), or Formula (Ib) and each additional therapeuticagents in its own separate pharmaceutical dosage formulation. Forexample, a compound of Formula (I), Formula (Ia), or Formula (Ib) and atherapeutic agent may be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent may be administered in separate oral dosage formulations.

[0472] Where separate dosage formulations are used, the compound ofFormula (I), Formula (Ia), or Formula (Ib) and one or more additionaltherapeutic agents may be administered at essentially the same time(e.g., concurrently) or at separately staggered times (e.g.,sequentially).

[0473] For example, the compounds of Formula (I), Formula (Ia), orFormula (Ib) may be used in combination with other therapies and drugsuseful for the treatment of obesity. For example, anti-obesity drugsinclude β-3 agonists such as CL-316,243; CB-1 antagonists; neuropeptideY5 inhibitors; appetite suppressants, such as, for example, sibutramine(Meridia); and lipase inhibitors, such as, for example, orlistat(Xenical). The compounds of the present invention may also beadministered in combination with a drug compound that modulatesdigestion and/or metabolism such as drugs that modulate thermogenesis,lipolysis, gut motility, fat absorption, and satiety.

[0474] In addition, the compounds of Formula (I), Formula (Ia), orFormula (Ib) may be administered in combination with one or more of thefollowing agents for the treatment of diabetes or diabetes-relateddisorders including PPAR ligands (agonists, antagonists), insulinsecretagogues, for example, sulfonylurea drugs and non-sulfonylureasecretagogues, α-glucosidase inhibitors, insulin sensitizers, hepaticglucose output lowering compounds, and insulin and insulin derivatives.Such therapies may be administered prior to, concurrently with, orfollowing administration of the compounds of the invention. Insulin andinsulin derivatives include both long and short acting forms andformulations of insulin. PPAR ligands may include agonists and/orantagonists of any of the PPAR receptors or combinations thereof. Forexample, PPAR ligands may include ligands of PPAR-α, PPAR-γ, PPAR-δ orany combination of two or three of the receptors of PPAR. PPAR ligandsinclude, for example, rosiglitazone, troglitazone, and pioglitazone.Sulfonylurea drugs include, for example, glyburide, glimepiride,chlorpropamide, tolbutamide, and glipizide. α-glucosidase inhibitorsthat may be useful in treating diabetes when administered with acompound of the invention include acarbose, miglitol, and voglibose.Insulin sensitizers that may be useful in treating diabetes includePPAR-γ agonists such as the glitazones (e.g., troglitazone,pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) andother thiazolidinedione and non-thiazolidinedione compounds; biguanidessuch as metformin and phenformin; protein tyrosine phosphatase-1B(PP-1B) inhibitors; dipeptidyl peptidase IV (DPP-IV) inhibitors, and11beta-HSD inhibitors. Hepatic glucose output lowering compounds thatmay be useful in treating diabetes when administered with a compound ofthe invention include glucagon anatgonists and metformin, such asGlucophage and Glucophage XR. Insulin secretagogues that may be usefulin treating diabetes when administered with a compound of the inventioninclude sulfonylurea and non-sulfonylurea drugs: GLP-1, GIP, PACAP,secretin, and derivatives thereof; nateglinide, meglitinide,repaglinide, glibenclamide, glimepiride, chlorpropamide, glipizide.GLP-1 includes derivatives of GLP-1 with longer half-lives than nativeGLP-1, such as, for example, fatty-acid derivatized GLP-1 and exendin.

[0475] Compounds of the invention may also be used in methods of theinvention in combination with drugs commonly used to treat lipiddisorders in patients. Such drugs include, but are not limited to,HMG-CoA reductase inhibitors, nicotinic acid, fatty acid loweringcompounds (e.g., acipimox); lipid lowering drugs (e.g., stanol esters,sterol glycosides such as tiqueside, and azetidinones such asezetimibe), ACAT inhibitors (such as avasimibe), bile acid sequestrants,bile acid reuptake inhibitors, microsomal triglyceride transportinhibitors, and fibric acid derivatives. HMG-CoA reductase inhibitorsinclude, for example, lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin, rivastatin, itavastatin, cerivastatin, and ZD-4522. Fibricacid derivatives include, for example, clofibrate, fenofibrate,bezafibrate, ciprofibrate, beclofibrate, etofibrate, and gemfibrozil.Sequestrants include, for example, cholestyramine, colestipol, anddialkylaminoalkyl derivatives of a cross-linked dextran.

[0476] Compounds of the invention may also be used in combination withanti-hypertensive drugs, such as, for example, β-blockers and ACEinhibitors. Examples of additional anti-hypertensive agents for use incombination with the compounds of the present invention include calciumchannel blockers (L-type and T-type; e.g., diltiazem, verapamil,nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide,hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril,zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists(e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g.,sitaxsentan, atrsentan, neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), and nitrates.

[0477] The compounds of Formula (I), Formula (Ia), and Formula (Ib) mayalso be utilized, in free base form or in compositions, as well as inresearch and diagnostics or as analytical reference standards, and thelike, which are well known in the art. Therefore, the present inventionincludes compositions which are comprised of an inert carrier and aneffective amount of a compound of Formula (I), Formula (Ia), or Formula(Ib), or a salt, or ester thereof. An inert carrier is any materialwhich does not interact with the compound to be carried and which lendssupport, means of conveyance, bulk, traceable material, and the like tothe compound to be carried. An effective amount of the compound is thatamount which produces a result or exerts an influence on the particularprocedure being performed.

[0478] It is anticipated that prodrug forms of the compounds of thisinvention will prove useful in certain circumstances, and such compoundsare also intended to fall within the scope of the invention. Prodrugforms may have advantages over the parent compounds exemplified herein,in that they are better absorbed, better distributed, more readilypenetrate the central nervous system, are more slowly metabolized orcleared, etc. Prodrug forms may also have formulation advantages interms of crystallinity or water solubility. For example, compounds ofthe invention having one or more hydroxyl groups may be converted toesters or carbonates bearing one or more carboxyl, hydroxyl or aminogroups, which are hydrolyzed at physiological pH values or are cleavedby endogenous esterases or lipases in vivo (see, e.g., U.S. Pat. Nos.4,942,184; 4,960,790; 5,817,840; and 5,824,701, all of which areincorporated herein by reference in their entirety, and referencestherein).

Pharmaceutical Compositions

[0479] Based on the above tests, or other well known assays used todetermine the efficacy for treatment of conditions identified above inmammals, and by comparison of these results with the results of knownmedicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

[0480] The total amount of the active ingredient to be administered maygenerally range from about 0.001 mg/kg to about 200 mg/kg, andpreferably from about 0.01 mg/kg to about 200 mg/kg body weight per day.A unit dosage may contain from about 0.05 mg to about 1500 mg of activeingredient, and may be administered one or more times per day. The dailydosage for administration by injection, including intravenous,intramuscular, subcutaneous, and parenteral injections, and use ofinfusion techniques may be from about 0.01 to about 200 mg/kg. The dailyrectal dosage regimen may be from 0.01 to 200 mg/kg of total bodyweight. The transdermal concentration may be that required to maintain adaily dose of from 0.01 to 200 mg/kg.

[0481] Of course, the specific initial and continuing dosage regimen foreach patient will vary according to the nature and severity of thecondition as determined by the attending diagnostician, the activity ofthe specific compound employed, the age of the patient, the diet of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt thereof may be ascertained bythose skilled in the art using conventional treatment tests.

[0482] The compounds of this invention may be utilized to achieve thedesired pharmacological effect by administration to a subject in needthereof in an appropriately formulated pharmaceutical composition. Asubject, for example, may be a mammal, including a human, in need oftreatment for a particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions which are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound identified by the methods described herein, or apharmaceutically acceptable salt or ester thereof. A pharmaceuticallyacceptable carrier is any carrier which is relatively non-toxic andinnocuous to a patient at concentrations consistent with effectiveactivity of the active ingredient so that any side effects ascribable tothe carrier do not vitiate the beneficial effects of the activeingredient. A pharmaceutically effective amount of a compound is thatamount which produces a result or exerts an influence on the particularcondition being treated. The compounds identified by the methodsdescribed herein may be administered with a pharmaceutically-acceptablecarrier using any effective conventional dosage unit forms, including,for example, immediate and timed release preparations, orally,parenterally, topically, or the like.

[0483] For oral administration, the compounds may be formulated intosolid or liquid preparations such as, for example, capsules, pills,tablets, troches, lozenges, melts, powders, solutions, suspensions, oremulsions, and may be prepared according to methods known to the art forthe manufacture of pharmaceutical compositions. The solid unit dosageforms may be a capsule which can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers such as lactose, sucrose, calciumphosphate, and corn starch.

[0484] In another embodiment, the compounds of this invention may betableted with conventional tablet bases such as lactose, sucrose, andcornstarch in combination with binders such as acacia, cornstarch, orgelatin; disintegrating agents intended to assist the break-up anddissolution of the tablet following administration such as potatostarch, alginic acid, corn starch, and guar gum; lubricants intended toimprove the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample, talc, stearic acid, or magnesium, calcium or zinc stearate;dyes; coloring agents; and flavoring agents intended to enhance theaesthetic qualities of the tablets and make them more acceptable to thepatient. Suitable excipients for use in oral liquid dosage forms includediluents such as water and alcohols, for example, ethanol, benzylalcohol, and polyethylene alcohols, either with or without the additionof a pharmaceutically acceptable surfactant, suspending agent, oremulsifying agent. Various other materials may be present as coatings orto otherwise modify the physical form of the dosage unit. For instancetablets, pills or capsules may be coated with shellac, sugar or both.

[0485] Dispersible powders and granules are suitable for the preparationof an aqueous suspension. They provide the active ingredient inadmixture with a dispersing or wetting agent, a suspending agent, andone or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, those sweetening, flavoring andcoloring agents described above, may also be present.

[0486] The pharmaceutical compositions of this invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil such as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived from fattyacids and hexitol anhydrides, for example, sorbitan monooleate, and (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

[0487] Oily suspensions may be formulated by suspending the activeingredient in a vegetable oil such as, for example, arachis oil, oliveoil, sesame oil, or coconut oil; or in a mineral oil such as liquidparaffin. The oily suspensions may contain a thickening agent such as,for example, beeswax, hard paraffin, or cetyl alcohol. The suspensionsmay also contain one or more preservatives, for example, ethyl orn-propyl p-hydroxybenzoate; one or more coloring agents; one or moreflavoring agents; and one or more sweetening agents such as sucrose orsaccharin.

[0488] Syrups and elixirs may be formulated with sweetening agents suchas, for example, glycerol, propylene glycol, sorbitol, or sucrose. Suchformulations may also contain a demulcent, and preservative, flavoringand coloring agents.

[0489] The compounds of this invention may also be administeredparenterally, that is, subcutaneously, intravenously, intramuscularly,or interperitoneally, as injectable dosages of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichmay be a sterile liquid or mixture of liquids such as water, saline,aqueous dextrose and related sugar solutions; an alcohol such asethanol, isopropanol, or hexadecyl alcohol; glycols such as propyleneglycol or polyethylene glycol; glycerol ketals such as2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such aspoly(ethyleneglycol) 400; an oil; a fatty acid; a fatty acid ester orglyceride; or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant such as a soap or adetergent, suspending agent such as pectin, carbomers, methycellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutical adjuvants.

[0490] Illustrative of oils which can be used in the parenteralformulations of this invention are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil,sesame oil, cottonseed oil, corn oil, olive oil, petrolatum, and mineraloil. Suitable fatty acids include oleic acid, stearic acid, andisostearic acid. Suitable fatty acid esters are, for example, ethyloleate and isopropyl myristate. Suitable soaps include fatty alkalimetal, ammonium, and triethanolamine salts and suitable detergentsinclude cationic detergents, for example, dimethyl dialkyl ammoniumhalides, alkyl pyridinium halides, and alkylamine acetates; anionicdetergents, for example, alkyl, aryl, and olefin sulfonates, alkyl,olefin, ether, and monoglyceride sulfates, and sulfosuccinates; nonionicdetergents, for example, fatty amine oxides, fatty acid alkanolamides,and polyoxyethylenepolypropylene copolymers; and amphoteric detergents,for example, alkyl-beta-aminopropionates, and 2-alkylimidazolinequarternary ammonium salts, as well as mixtures.

[0491] The parenteral compositions of this invention may typicallycontain from about 0.5% to about 25% by weight of the active ingredientin solution. Preservatives and buffers may also be used advantageously.In order to minimize or eliminate irritation at the site of injection,such compositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) of from about 12 to about 17. Thequantity of surfactant in such formulation ranges from about 5% to about15% by weight. The surfactant can be a single component having the aboveHLB or can be a mixture of two or more components having the desiredHLB.

[0492] Illustrative of surfactants used in parenteral formulations arethe class of polyethylene sorbitan fatty acid esters, for example,sorbitan monooleate and the high molecular weight adducts of ethyleneoxide with a hydrophobic base, formed by the condensation of propyleneoxide with propylene glycol.

[0493] The pharmaceutical compositions may be in the form of sterileinjectable aqueous suspensions. Such suspensions may be formulatedaccording to known methods using suitable dispersing or wetting agentsand suspending agents such as, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents which may be a naturally occurringphosphatide such as lecithin, a condensation product of an alkyleneoxide with a fatty acid, for example, polyoxyethylene stearate, acondensation product of ethylene oxide with a long chain aliphaticalcohol, for example, heptadecaethyleneoxycetanol, a condensationproduct of ethylene oxide with a partial ester derived form a fatty acidand a hexitol such as polyoxyethylene sorbitol monooleate, or acondensation product of an ethylene oxide with a partial ester derivedfrom a fatty acid and a hexitol anhydride, for example polyoxyethylenesorbitan monooleate.

[0494] The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally acceptablediluent or solvent. Diluents and solvents that may be employed are, forexample, water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile fixed oils are conventionally employed assolvents or suspending media. For this purpose, any bland, fixed oil maybe employed including synthetic mono or diglycerides. In addition, fattyacids such as oleic acid may be used in the preparation of injectables.

[0495] A composition of the invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions may be prepared by mixing the drug with a suitablenon-irritation excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such material are, for example, cocoa butter andpolyethylene glycol.

[0496] Another formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art (see, e.g.,U.S. Pat. No. 5,023,252, incorporated herein by reference). Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

[0497] It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. For example, directtechniques for administering a drug directly to the brain usuallyinvolve placement of a drug delivery catheter into the patient'sventricular system to bypass the blood-brain barrier. One suchimplantable delivery system, used for the transport of agents tospecific anatomical regions of the body, is described in U.S. Pat. No.5,011,472, incorporated herein by reference.

[0498] The compositions of the invention may also contain otherconventional pharmaceutically acceptable compounding ingredients,generally referred to as carriers or diluents, as necessary or desired.Any of the compositions of this invention may be preserved by theaddition of an antioxidant such as ascorbic acid or by other suitablepreservatives. Conventional procedures for preparing such compositionsin appropriate dosage forms can be utilized.

[0499] Commonly used pharmaceutical ingredients which may be used asappropriate to formulate the composition for its intended route ofadministration include: acidifying agents, for example, but are notlimited to, acetic acid, citric acid, fumaric acid, hydrochloric acid,nitric acid; and alkalinizing agents such as, but are not limited to,ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine.

[0500] Other pharmaceutical ingredients include, for example, but arenot limited to, adsorbents (e.g., powdered cellulose and activatedcharcoal); aerosol propellants (e.g., carbon dioxide, CCl₂F₂,F₂ClC—CClF₂ and CClF₃); air displacement agents (e.g., nitrogen andargon); antifungal preservatives (e.g., benzoic acid, butylparaben,ethylparaben, methylparaben, propylparaben, sodium benzoate);antimicrobial preservatives (e.g., benzalkonium chloride, benzethoniumchloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol,phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal);antioxidants (e.g., ascorbic acid, ascorbyl palmitate, butylatedhydroxyani sole, butylated hydroxytoluene, hypophosphorus acid,monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite,sodium formaldehyde sulfoxylate, sodium metabisulfite); bindingmaterials (e.g., block polymers, natural and synthetic rubber,polyacrylates, polyurethanes, silicones and styrene-butadienecopolymers); buffering agents (e.g., potassium metaphosphate, potassiumphosphate monobasic, sodium acetate, sodium citrate anhydrous and sodiumcitrate dihydrate); carrying agents (e.g., acacia syrup, aromatic syrup,aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, cornoil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chlorideinjection and bacteriostatic water for injection); chelating agents(e.g., edetate disodium and edetic acid); colorants (e.g., FD&C Red No.3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5,D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (e.g., bentonite); emulsifying agents (but are notlimited to, acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate,lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulatingagents (e.g., gelatin and cellulose acetate phthalate); flavorants(e.g., anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermintoil and vanillin); humectants (e.g., glycerin, propylene glycol andsorbitol); levigating agents (e.g., mineral oil and glycerin); oils(e.g., arachis oil, mineral oil, olive oil, peanut oil, sesame oil andvegetable oil); ointment bases (e.g., lanolin, hydrophilic ointment,polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, whiteointment, yellow ointment, and rose water ointment); penetrationenhancers (transdermal delivery) (e.g., monohydroxy or polyhydroxyalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas); plasticizers (e.g., diethyl phthalate andglycerin); solvents (e.g., alcohol, corn oil, cottonseed oil, glycerin,isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water,water for injection, sterile water for injection and sterile water forirrigation); stiffening agents (e.g., cetyl alcohol, cetyl esters wax,microcrystalline wax, paraffin, stearyl alcohol, white wax and yellowwax); suppository bases (e.g., cocoa butter and polyethylene glycols(mixtures)); surfactants (e.g., benzalkonium chloride, nonoxynol 10,oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitanmonopalmitate); suspending agents (e.g., agar, bentonite, carbomers,carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose,tragacanth and veegum); sweetening e.g., aspartame, dextrose, glycerin,mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose);tablet anti-adherents (e.g., magnesium stearate and talc); tabletbinders (e.g., acacia, alginic acid, carboxymethylcellulose sodium,compressible sugar, ethylcellulose, gelatin, liquid glucose,methylcellulose, povidone and pregelatinized starch); tablet and capsulediluents (e.g., dibasic calcium phosphate, kaolin, lactose, mannitol,microcrystalline cellulose, powdered cellulose, precipitated calciumcarbonate, sodium carbonate, sodium phosphate, sorbitol and starch);tablet coating agents (e.g., liquid glucose, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose,ethylcellulose, cellulose acetate phthalate and shellac); tablet directcompression excipients (e.g., dibasic calcium phosphate); tabletdisintegrants (e.g., alginic acid, carboxymethylcellulose calcium,microcrystalline cellulose, polacrillin potassium, sodium alginate,sodium starch glycollate and starch); tablet glidants (e.g., colloidalsilica, corn starch and talc); tablet lubricants (e.g., calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate); tablet/capsule opaquants (e.g., titanium dioxide); tabletpolishing agents (e.g., camuba wax and white wax); thickening agents(e.g., beeswax, cetyl alcohol and paraffin); tonicity agents (e.g.,dextrose and sodium chloride);viscosity increasing agents (e.g., alginicacid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, povidone, sodium alginate and tragacanth); and wettingagents (e.g., heptadecaethylene oxycetanol, lecithins, polyethylenesorbitol monooleate, polyoxyethylene sorbitol monooleate, andpolyoxyethylene stearate).

[0501] The compounds identified by the methods described herein may beadministered as the sole pharmaceutical agent or in combination with oneor more other pharmaceutical agents where the combination causes nounacceptable adverse effects. For example, the compounds of thisinvention can be combined with known anti-obesity, or with knownantidiabetic or other indication agents, and the like, as well as withadmixtures and combinations thereof.

[0502] The compounds identified by the methods described herein may alsobe utilized, in free base form or in compositions, in research anddiagnostics, or as analytical reference standards, and the like.Therefore, the present invention includes compositions which arecomprised of an inert carrier and an effective amount of a compoundidentified by the methods described herein, or a salt or ester thereof.An inert carrier is any material which does not interact with thecompound to be carried and which lends support, means of conveyance,bulk, traceable material, and the like to the compound to be carried. Aneffective amount of compound is that amount which produces a result orexerts an influence on the particular procedure being performed.

[0503] Formulations suitable for subcutaneous, intravenous,intramuscular, and the like; suitable pharmaceutical carriers; andtechniques for formulation and administration may be prepared by any ofthe methods well known in the art (see, e.g., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., 20^(th) edition, 2000).

Biological Activity of the Compounds

[0504] In order that this invention may be better understood, thefollowing examples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

[0505] Demonstration of the activity of the compounds of the presentinvention may be accomplished through in vitro, ex vivo, and in vivoassays that are well known in the art. For example, to demonstrate theefficacy of a pharmaceutical agent for the treatment of obesity andrelated disorders, the following assays may be used.

Evaluation of Compound Effect on the Inhibition of DGAT-1 EnzymeActivity

[0506] The human DGAT-1 gene (see, e.g., U.S. Pat. No. 6,100,077) wasisolated from a human cDNA library by PCR. Recombinant AcNPV baculoviruswas constructed in which the gene for occlusion body forming proteinpolyhedrin was replaced with the DGAT-1 gene. The DGAT-1 gene sequencewas inserted into the AcNPV genome 3′ to the polyhedrin promotersequence placing DGAT-1 under the transcriptional control of thepolyhedrin promoter. Spodoptera frugiperda-derived Sf9 insect cells wereinfected with DGAT-1-containing recombinant baculovirus at themultiplicity of infection of 5 and harvested 48 h post-infection.DGAT-1-expressing insect cells were homogenized in 10 mM Tris, 250 mMsucrose, pH 7.5 at the concentration of 100 mg of wet cell biomass permL. The homogenate was centrifuged at 25,000 g for 30 minutes. The25,000 g pellet was discarded and the supernatant was centrifuged at100,000 g for 1 h. The 100,000 g supernatant was discarded and the100,000 g DGAT-1-containing membrane pellet was re-suspended in 10 mMTris, 50% (v/v) glycerol pH 7.5.

[0507] DGAT-1 enzyme activity was determined by a phase partitioningprotocol. Specifically, DGAT-1 containing membranes were incubated in 20mM didecanoyl glycerol, 5 mM ¹⁴C-decanoyl-CoA, 2 mM MgCl₂, 0.04% BSA, 20mM HEPES, pH 7.5 buffer in the presence of varying concentrations ofinhibitors. Assays were performed in 100 μl volumes in 96-wellmicrotiter plates 0.5 μg total membrane protein per well. The assay wasinitiated by substrate and mixed gently for 1 h at ambient temperature.Activity was quenched by the addition of 25 μl of 0.1% phosphoric acidsolution. Selective extraction of the hydrophobic tridecanolyglycerolproduct was accomplished by the addition of 150 μl phase partitioningscintillation fluid Microscint® (Packard, Inc.) and vigorous mixing for30 minutes. Quantification of the product was accomplished by aMicroBeta® scintillation counter (Wallac, Inc.) after settling forapproximately 16 h at ambient temperatures.

Evaluation of Compound Effect on the Inhibition of Cellular TriplycerideDeposition

[0508] The cell-based assay for DGAT-1 was conducted with humancolorectal adenocarcinoma cells HT-29 (HTB-38, ATCC). HT-29 cells weregrown in 75 cm² plate until ˜90% confluent in DMEM media with 10% FBS,PSF, glutamine, and 10 mM acetate. Cells were then re-plated in 24-wellplates to give 1:1.2 dilution and grown approximately 16 h.Triacylglyceride formation was stimulated by the addition of lauric acidto 0.01% final concentration in the presence of varying concentrationsof inhibitors. After 6 h, cells were released from the plate by trypsin,collected by centrifugation, re-suspended in water, transferred to glassHPLC, frozen at −70° C., and lyophilized. Freeze dried cell pellets werere-suspended in 150 μl HPLC grade tetrahydrofuran and sealed in thevials. Vials were sonicated for 30 minutes with heating in a sonicatingwater bath (Fisher, Inc.). Cellular triacylglycerides were quantified byHPLC (HP1100, Agilent, Inc.) utilizing evaporative light-scatteringdetection (PL-ELS 1000, Polymer Labs, Inc.). Chromatographic separationwas accomplished by 30 to 100% B buffer in 4 minutes followed by 3minutes at 100% B buffer using a PLRP S 100 column (5 micron, 150×4.6mm, Polymer Labs, Inc.) at 50° C. (A: 50% acetonitrile, 2.5% methanol,B: 100% tetrahydrofuran). Sample injections were 20 μl and the detectorwas set at 0.4 SLM, 40° C. nebulizer and 80° C. evaporator. Non-polarfatty acids and glycerol lipids were identified and quantified by usingcommercially available standards.

Evaluation of Compound Efficacy on the Reduction of Body Weight inDiet-Induced Obese Mice

[0509] The purpose of this protocol is to determine the effect ofchronic administration of a compound on the body weight of mice madeobese by exposure to a 45% kcal/g high fat diet for more than 10 weeks.The body weight of mice selected for these studies was higher than threestandard deviations from the weight of a control group of mice fedstandard low fat (5-6% fat) mouse chow. Diet-induced obese (DIO) animalshave been used frequently in the determination of compound efficacy inthe reduction of body weight (see, e.g., Brown, et al., Brit. J.Pharmacol. 132:1898-1904, 2001; Guerre-Millo, et al., J. Biol. Chem.275(22): 16638-42, 2000; Han, et al., Intl. J. Obesity and RelatedMetabolic Disorders 23(2):174-79, 1999; Surwit, et al., Endocrinol.141(10):3630-37, 2000).

[0510] This animal model has been successfully used in theidentification and characterization of the efficacy profile of compoundsthat are or have been used in the management of body weight in obesehumans (see, e.g., Brown, et al., 2001; Guerre-Millo, et al., 2000; Han,et al., 1999).

[0511] A typical study included 60-80 male C57b1/J6 mice (n=10/treatmentgroup) with an average body weight of approximately 45 g. Mice were keptin standard animal rooms under controlled temperature and humidity and a12 hour/12 hour light/dark cycle. Water and food were continuouslyavailable. Mice were individually housed. Animals were sham dosed withstudy vehicle for at least four days before the recording of two-daybaseline measurements of body weight and 24-hour food and waterconsumption. Mice were assigned to one of 6-8 treatment groups basedupon their body weight on baseline. The groups were set up so that themean and standard error of the mean of body weight were similar.

[0512] Animals were orally gavaged (5 mL/kg) daily before the dark phaseof the light/dark cycle for a pre-determined number of days (typically8-14 days) with their assigned dose/compound. Body weight, and food andwater consumption were measured. Data was analyzed using appropriatestatistics following the research design. On the final day, animals wereeuthanized using CO₂ inhalation.

[0513] Compounds were typically dosed at 5 or 10 mg/kg p.o. q.d. as asuspension formulation in 50:50 PEG/water, or p.o. b.i.d. as asuspension formulation in 0.5% methylcellulose, and compounds wereconsidered to be active if a statistically significant reduction in bodyweight was observed for the treated animals after a treatment period ofat least seven days, relative to vehicle-treated control animals.

[0514] The structures, materials, compositions, and methods describedherein are intended to be representative examples of the invention, andit will be understood that the scope of the invention is not limited bythe scope of the examples. Those skilled in the art will recognize thatthe invention may be practiced with variations on the disclosedstructures, materials, compositions and methods, and such variations areregarded as within the ambit of the invention.

What is claimed:
 1. A compound of Formula (I)

wherein Q is O, S, or NR⁵; A is a linker selected from

wherein p is 1 or 2 and

wherein m is 0 and n is 1, 2, 3, or 4, or m is 1 and n is 1, 2, or 3,and wherein said linker is optionally substituted by one or two R⁸groups; R¹ and R² are independently selected from hydrogen, halo,(C₁-C₆)alkyl, and (C₁-C₆)alkoxy; R³ is selected from hydrogen,(C₁-C₆)alkyl optionally substituted by hydroxy, and phenyl optionallysubstituted with (C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo; R⁴ is selectedfrom hydrogen, nitro, and (C₁-C₆)alkyl; or R³ and R⁴ may, when takentogether with the carbon atoms to which they are attached, form abenzene ring optionally substituted with up to two substituents selectedfrom halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,bis[(C₁-C₆)alkyl]aminocarbonyl, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, bis[(C₁-C₆)alkyl]aminosulfonyl,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylsulfonylamino,hydroxy-(C₂-C₆)alkylaminocarbonyl, 1-morpholinylcarbonyl, and1-piperidinylcarbonyl, and when two of said benzene ring substituentsare (C₁-C₆)alkyl and are attached to adjacent carbon atoms of thebenzene ring, they may be joined together to form a 5-7-memberedcarbocyclic ring; R⁵ is hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen; R⁷ ishydrogen or (C₁-C₆)alkyl optionally substituted with (C₁-C₆)alkoxy, bis[(C₁-C₃)alkyl]amino or phenyl optionally substituted with halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or cyano; or R⁶ and R⁷ are both(C₁-C₆)alkyl; or R⁶ and R⁷ may form, together with the carbon atom towhich they are attached, a 3- to 5-membered carbocyclic ring, or a6-membered ring represented by

wherein W is CH₂, C(CH₃)₂, O, NR⁹, S, or SO₂; R⁸ is (C₁-C₆)alkyl; and R⁹is hydrogen or (C₁-C₆)alkyl; or the pharmaceutically acceptable saltsand esters thereof.
 2. The compound of claim 1, wherein Q is NR⁵; A is

wherein p is 1 or 2, and wherein said linker is optionally substitutedby one or two R⁸ groups; R³ and R⁴ may, when taken together with thecarbon atoms to which they are attached, form a benzene ring optionallysubstituted with up to two substituents selected from halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,bis[(C₁-C₆)alkyl]aminocarbonyl, arninosulfonyl,(C₁-C₆)alkylamninosulfonyl, bis[(C₁-C₆)alkyl]aminosulfonyl,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylsulfonylamino,hydroxy-(C₂-C₆)alkylaminocarbonyl, 1-morpholinylcarbonyl, and1-piperidinylcarbonyl; and R¹, R², R⁵, R⁶, R⁷, R⁸, R⁹, and W are asdefined in claim
 1. 3. The compound of claim 1, wherein Q is NR⁵; A is

wherein m is 0 and n is 1, 2, 3, or 4, or m is 1 and n is 1, 2, or 3,and wherein said linker is optionally substituted by one or two R⁸groups; R³ and R⁴ may, when taken together with the carbon atoms towhich they are attached, form a benzene ring optionally substituted withup to two substituents selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,nitro, cyano, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, bis[(C₁-C₆)alkyl]aminocarbonyl,aminosulfonyl, (C₁-C₆)alkylaminosulfonyl,bis[(C₁-C₆)alkyl]aminosulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylsulfonylamino, hydroxy-(C₂-C₆)alkylaminocarbonyl,1-morpholinylcarbonyl, and 1-piperidinylcarbonyl; and R¹, R², R⁵, and R⁸are as defined in claim
 1. 4. The compound of claim 1, wherein Q is O; Ais

wherein p is 1 or 2, and wherein said linker is optionally substitutedby one or two R⁸ groups; R³ and R⁴ may, when taken together with thecarbon atoms to which they are attached, form a benzene ring optionallysubstituted with up to two substituents selected from halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,bis[(C₁-C₆)alkyl]aminocarbonyl, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, bis[(C₁-C₆)alkyl]aminosulfonyl,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylsulfonylamino,hydroxy-(C₂-C₆)alkylaminocarbonyl, 1-morpholinylcarbonyl, and1-piperidinylcarbonyl; and R¹, R², R⁶, R⁷, R⁸, R⁹, and W are as definedin claim
 1. 5. The compound of claim 1, wherein Q is O; A is

wherein m is 0 and n is 1, 2, 3, or 4, or m is 1 and n is 1, 2, or 3,and wherein said linker is optionally substituted by one or two R⁸groups; R³ and R⁴ may, when taken together with the carbon atoms towhich they are attached, form a benzene ring optionally substituted withup to two substituents selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,nitro, cyano, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, bis[(C₁-C₆)alkyl]aminocarbonyl,aminosulfonyl, (C₁-C₆)alkylaminosulfonyl,bis[(C₁-C₆)alkyl]aminosulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylsulfonylamino, hydroxy-(C₂-C₆)alkylaminocarbonyl,1-morpholinylcarbonyl, and 1-piperidinylcarbonyl; and R¹, R², and R⁸ areas defined in claim
 1. 6. The compound of claim 1, wherein Q is S; A is

wherein p is 1 or 2, and wherein said linker is optionally substitutedby one or two R⁸ groups; R³ and R⁴ may, when taken together with thecarbon atoms to which they are attached, form a benzene ring optionallysubstituted with up to two substituents selected from halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,bis[(C₁-C₆)alkyl]aminocarbonyl, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, bis[(C₁-C₆)alkyl]aminosulfonyl,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylsulfonylamino,hydroxy-(C₂-C₆)alkylaminocarbonyl, 1-morpholinylcarbonyl, and1-piperidinylcarbonyl; and R¹, R², R⁶, R⁷, R⁸, R⁹, and W are as definedin claim
 1. 7. The compound of claim 1, wherein Q is S; A is

wherein m is 0 and n is 1, 2, 3, or 4, or m is 1 and n is 1,2, or 3, andwherein said linker is optionally substituted by one or two R⁸ groups;R³ and R⁴ may, when taken together with the carbon atoms to which theyare attached, form a benzene ring optionally substituted with up to twosubstituents selected from halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro,cyano, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, aminocarbonyl,(C₁-C₆)alkylaminocarbonyl, bis[(C₁-C₆)alkyl]aminocarbonyl,aminosulfonyl, (C₁-C₆)alkylaminosulfonyl,bis[(C₁-C₆)alkyl]aminosulfonyl, (C₁-C₆)alkylcarbonylamino,(C₁-C₆)alkylsulfonylamino, hydroxy-(C₂-C₆)alkylaminocarbonyl,1-morpholinylcarbonyl, and 1-piperidinylcarbonyl; and R¹, R², and R⁸ areas defined in claim
 1. 8. The compound of claim 1 selected from thegroup consisting of:4-[4′-(1H-benzimidazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid;4-{4′-[(5-methoxy-1H-benzimidazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;trans-2-{[4′-(1H-benzimidazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylicacid;trans-2-({4′-[(5-methoxy-1H-benzimidazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)trans-2-[(4′-{[5-(trifluoromethyl)-1H-benzimidazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid;trans-2-({4′-[(5,6-difluoro-1H-benzimidazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-(1R,2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}-cyclopentane-carboxylicacid;trans-(1R,2R)-2-({3′-fluoro-4′-[(5-methoxy-1H-benzimidazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid; andtrans-(1R,2R)-2-[(3′-fluoro-4′-{[5-(trifluoromethyl)-1H-benzimidazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid.
 9. The compound of claim 1 selected from the group consisting of:4-[4′-(1,3-benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]4-oxo-2-(2-phenylethyl)butanoicacid;2,2-dimethyl-4-{4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid;4-{4′-[(6-chloro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;4-{4′-[(6-methoxy-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;2,2-dimethyl-4-{4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid;2,2-dimethyl-4-{4′-[(4-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid;2,2-dimethyl-4-oxo-4-[4′-(5,6,7,8-tetrahydronaphtho[2,3-d][1,3]oxazol-2-ylamino)-1,1′-biphenyl-4-yl]butanoicacid;4-{4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;4-{4′-[(5-isopropyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;2,2-dimethyl-4-oxo-4-{4′-[(5-propyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}butanoicacid;trans-2-({4′-[(6-chloro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-chloro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-methoxy-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(5,6-dimethyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-{[4′-(1,3-benzoxazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylicacid;trans-2-({4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-(1R,2R)-2-({4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(6-chloro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(6-chloro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1R,2R)-2-[(4′-{[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(6-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1S,2S)-2-({4′-[(6-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-2-({4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;trans-2-({4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;4-{4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxo-2-(2-phenylethyl)butanoic acid;trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-2-({4′-[(6-chloro-1,3-benzoxazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-(1R,2R)-2-({3′-fluoro-4′-[(5-fluoro-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-(1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-(1R,2R)-2-({3′-fluoro-4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-(1R,2R)-2-[(3′-fluoro-4′-{[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid.
 10. The compound of claim 1 selected from the group consisting of:4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoicacid;4-{4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;4-{4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;2,2-dimethyl-4-oxo-4-[4′-(1,3-thiazol-2-ylamino)-1,1′-biphenyl-4-yl]butanoicacid;4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2-(2-methoxyethyl)-4-oxobutanoicacid;4-{4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-(2-methoxyethyl)-4-oxobutanoicacid;4-{4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-(2-methoxyethyl)-4-oxobutanoicacid;trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;4-{4′-[(5-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;2,2-dimethyl-4-{4′-[(6-nitro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid;4-{4′-[(4-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;trans-(1R,2R)-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylicacid;trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylicacid;4-{4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxo-2-(2-phenylethyl)butanoic acid;2-(2-{4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-oxoethyl)pentanoicacid;trans-2-({4′-[(5-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-2-({4′-[(6-nitro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(4-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;4-{4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2-[2-(dimethylamino)ethyl]4-oxobutanoic acid;2-[2-(dimethylamino)ethyl]4-{4′-[(5-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid;2-[2-(dimethylamino)ethyl]4-{4′-[(6-nitro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoicacid;trans-2-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-ethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-(1R,2R)-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1S,2S)-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;2,2-dimethyl-4-{4′-[(5-nitro-1,3-thiazol-2-yl)amino]-1,1′-biphenyl-4-yl}4-oxobutanoicacid;4-(4′-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoicacid;trans-(1R,2R)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-(1S,2S)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;cis-3-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylicacidcis-3-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;trans-2-[(4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1S,2S)-2-({4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-(1S,2S)-2-({4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacid;trans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-2-({4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-[(4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]-cyclopentane-carboxylicacid;trans-2-({4′-[(5-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(5,7-dimethyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-[(4′-{[6-(methylsulfonyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]-cyclopentane-carboxylicacid;trans-2-({4′-[(5,6-dimethyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;4-{4′-[(6-ethoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;4-{4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-2,2-dimethyl-4-oxobutanoicacid;trans-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylic acid;trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-(1R,2R)-2-[(4′-{[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-carbonyl]cyclopentane-carboxylicacid;trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclopropane-carboxylicacid;trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexane-carboxylic acid;trans-2-({4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;trans-2-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;trans-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;trans-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylic acid;trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]carbonyl}cyclobutane-carboxylicacid;trans-2-({4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutane-carboxylic acid;trans-2-({4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutane-carboxylic acid;trans-(1R,2R)-2-({4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacid;trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-(1R,2R)-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-(1R,2R)-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-2-{[4′-1,3-benzothiazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclopentane-carboxylicacid;trans-(1R,2R)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-(1S,2S)-2-({4′-[(4,6-difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid;trans-(1R,2R)-2-({3′-fluoro-4′-[(5-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}trans-(1R,2R)-2-({3′-fluoro-4′-[(4-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentane-carboxylicacidtrans-(1R,2R)-2-({4′-[(5-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacidtrans-(1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}trans-(1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}-carbonyl)cyclopentane-carboxylicacidtrans-(1R,2R)-2-({4′-[(5,7-dimethyl-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacidtrans-(1R,2R)-2-({4′-[(5,7-difluoro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacidtrans-(1R,2R)-2-[(3′-fluoro-4′-{[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino)}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid;trans-(1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentane-carboxylicacid;trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclobutane-carboxylicacidtrans-2-{[4′-(1,3-benzothiazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclobutane-carboxylicacid;trans-2-{[4′-(1,3-benzothiazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]carbonyl}cyclopropane-carboxylicacid;trans-2-({3′-fluoro-4′-[(6-methoxy-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopropane-carboxylicacidtrans-(1R,2R)-2-({3′-fluoro-4′-[(6-isopropyl-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentane-carboxylicacidtrans-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amnino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentane-carboxylicacidtrans-2-[(3′-fluoro-4′-{[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)-carbonyl]cyclopentane-carboxylicacid;4-{4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-3′-fluoro-1,1′-biphenyl-4-yl}4-oxo-2-(2-phenylethyl)butanoicacid; and(1R,2R)-2-[{3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}(hydroxy)-methyl]cyclopentanecarboxylicacid.
 11. A compound of Formula (Ia)

wherein Q is O, S, or NR⁵; A is a linker selected from

wherein p is 1 or 2 and

wherein m is 0 and n is 1, 2, 3, or 4, or m is 1 and n is 1, 2, or 3,and wherein said linker is optionally substituted by one or two R⁸groups; R¹and R² are independently selected from hydrogen, halo,(C₁-C₆)alkyl, and (C₁-C₆)alkoxy; R³ is selected from hydrogen,(C₁-C₆)alkyl optionally substituted by hydroxy, and phenyl optionallysubstituted with (C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo; R⁴ is selectedfrom hydrogen, nitro, and (C₁-C₆)alkyl; or R³ and R⁴ may, when takentogether with the carbon atoms to which they are attached, form abenzene ring optionally substituted with up to two substituents selectedfrom halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,bis[(C₁-C₆)alkyl]aminocarbonyl, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, bis[(C₁-C₆)alkyl]aminosulfonyl,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylsulfonylamino,hydroxy-(C₂-C₆)alkylaminocarbonyl, 1-morpholinylcarbonyl, and1-piperidinylcarbonyl, and when two of said benzene ring substituentsare (C₁-C₆)alkyl and are attached to adjacent carbon atoms of thebenzene ring, they may be joined together to form a 5-7-memberedcarbocyclic ring; R⁵ is hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen; R⁷ ishydrogen or (C₁-C₆)alkyl optionally substituted with (C₁-C₆)alkoxy,bis[(C₁-C₃)alkyl]amino or phenyl optionally substituted with halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or cyano; or R⁶ and R⁷ are both(C₁-C₆)alkyl; or R⁶ and R⁷ may form, together with the carbon atom towhich they are attached, a 3- to 5-membered carbocyclic ring, or a6-membered ring represented by

wherein W is CH₂, C(CH₃)₂, O, NR⁹, S, or SO₂; R⁸ is (C₁-C₆)alkyl; and R⁹is hydrogen or (C₁-C₆)alkyl; or the pharmaceutical salts and estersthereof.
 12. A compound of Formula (Ib)

wherein Q is O, S, or NR⁵; A is a linker selected from

wherein p is 1 or 2 and

wherein m is 0 and n is 1, 2, 3, or 4, or m is 1 and n is 1, 2, or 3,and wherein said linker is optionally substituted by one or two R⁸groups; R¹and R² are independently selected from hydrogen, halo,(C₁-C₆)alkyl, and (C₁-C₆)alkoxy; R³ is selected from hydrogen,(C₁-C₆)alkyl optionally substituted by hydroxy, and phenyl optionallysubstituted with (C₁-C₆)alkyl, (C₁-C₆)alkoxy, or halo; R⁴ is selectedfrom hydrogen, nitro, and (C₁-C₆)alkyl; or R³ and R⁴ may, when takentogether with the carbon atoms to which they are attached, form abenzene ring optionally substituted with up to two substituents selectedfrom halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, nitro, cyano, (C₁-C₆)haloalkyl,(C₁-C₆)haloalkoxy, aminocarbonyl, (C₁-C₆)alkylaminocarbonyl,bis[(C₁-C₆)alkyl]aminocarbonyl, aminosulfonyl,(C₁-C₆)alkylaminosulfonyl, bis[(C₁-C₆)alkyl]aminosulfonyl,(C₁-C₆)alkylcarbonylamino, (C₁-C₆)alkylsulfonylamino,hydroxy-(C₂-C₆)alkylaminocarbonyl, 1-morpholinylcarbonyl, and1-piperidinylcarbonyl, and when two of said benzene ring substituentsare (C₁-C₆)alkyl and are attached to adjacent carbon atoms of thebenzene ring, they may be joined together to form a 5-7-memberedcarbocyclic ring; R⁵ is hydrogen or (C₁-C₆)alkyl; R⁶ is hydrogen; R⁷ ishydrogen or (C₁-C₆)alkyl optionally substituted with (C₁-C₆)alkoxy,bis[(C₁-C₃)alkyl]amino or phenyl optionally substituted with halo,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, or cyano; or R⁶ and R⁷ are both(C₁-C₆)alkyl; or R⁶ and R⁷ may form, together with the carbon atom towhich they are attached, a 3- to 5-membered carbocyclic ring, or a6-membered ring represented by

wherein W is CH₂, C(CH₃)₂, O, NR⁹, S, or SO₂; R⁸ is (C₁-C₆)alkyl; and R⁹is hydrogen or (C₁-C₆)alkyl; or pharmaceutical salts and esters thereof.13. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltor ester, in combination with a pharmaceutically acceptable carrier. 14.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltor ester thereof, in combination with a pharmaceutically acceptablecarrier and one or more pharmaceutical agents.
 15. The pharmaceuticalcomposition of claim 14, wherein said pharmaceutical agent is ananti-obesity agent selected from the group consisting of β-3 agonists,CB-1 antagonists, neuropeptide Y5 inhibitors, appetite suppressants, andlipase inhibitors.
 16. The pharmaceutical composition of claim 14,wherein said pharmaceutical agent is an agent for the treatment ofdiabetes selected from the group consisting of insulin, insulinderivatives, PPAR ligands, sulfonylurea drugs, α-glucosidase inhibitors,biguanides, PTP-1B inhibitors, DPP-IV inhibitors, 11-beta-HSDinhibitors, GLP-1 and GLP-1 derivatives, GIP and GIP derivatives, PACAPand PACAP derivatives, and secretin and secretin derivatives.
 17. Thepharmaceutical composition of claim 14, wherein said pharmaceuticalagent is an agent for the treatment of lipid disorders selected from thegroup consisting of HMG-CoA inhibitors, nicotinic acid, fatty acidlowering compounds, lipid lowering drugs, ACAT inhibitors, bilesequestrants, bile acid reuptake inhibitors, microsomal triglyceridetransport inhibitors, and fibric acid derivatives.
 18. Thepharmaceutical composition of claim 14, wherein said pharmaceuticalagent is an anti-hypertensive agent selected from the group consistingof β-blockers, calcium channel blockers, diuretics, renin inhibitors,ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists, andnitrates.
 19. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 8, 9, 10, 11, or 12, or apharmaceutically acceptable salt or ester, in combination with apharmaceutically acceptable carrier.
 20. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 8,9, 10, 11, or 12, or a pharmaceutically acceptable salt or esterthereof, in combination with a pharmaceutically acceptable carrier andone or more pharmaceutical agents.
 21. A method of treating obesitycomprising the step of administering to a subject in need thereof atherapeutically effective amount of a compound of claim 1 or acomposition of claim
 13. 22. A method of inducing weight loss comprisingthe step of administering to a subject in need thereof a therapeuticallyeffective amount of a compound of claim 1 or a composition of claim 13.23. A method of preventing weight gain comprising the step ofadministering to a subject in need thereof a therapeutically effectiveamount of a compound of claim 1 or a composition of claim
 13. 24. Amethod of treating obesity-related disorders comprising the step ofadministering to a subject in need thereof a therapeutically effectiveamount of a compound of claim 1 or a composition of claim
 13. 25. Themethod of claim 24, wherein said obesity-related disorder is selectedfrom the group consisting of dyslipidemia, cholesterol gallstones,gallbladder disease, gout, cancer, menstrual abnormalities, infertility,polycystic ovaries, osteoarthritis, sleep apnea, hypertriglyceridemia,Syndrome X, type 2 diabetes, atherosclerotic diseases, hyperlipidemia,hypercholesteremia, low HDL levels, hypertension, cardiovasculardisease, coronary heart disease, coronary artery disease,cerebrovascular disease, stroke, and peripheral vessel disease.
 26. Amethod of treating obesity comprising the step of administering to asubject in need thereof a therapeutically effective amount of a compoundof claim 1 in combination with one or more pharmaceutical agents. 27.The method of claim 26, wherein the compound of claim 1 and one or morepharmaceutical agents are administered as a single pharmaceutical dosageformulation.
 28. A method of treating obesity comprising the step ofadministering to a subject in need thereof a therapeutically effectiveamount of a composition of claim 14, 15, 16, 17, or
 18. 29. A method oftreating obesity-related disorders comprising the step of administeringto a subject in need thereof a therapeutically effective amount of acomposition of claim 14, 15, 16, 17, or
 18. 30. Compounds according toclaim 1 for the treatment and/or prophylaxis of obesity andobesity-related disorders.
 31. Medicament containing at least onecompound according to claim 1 in combination with at least onepharmaceutically acceptable, pharmaceutically safe carrier or excipient.32. Use of compounds according to claim 1 for manufacturing a medicamentfor the treatment and/or prophylaxis of obesity and obesity-relateddisorders.
 33. Medicaments according to claim 31 for the treatmentand/or prophylaxis of obesity.
 34. A process for the preparation of acompound of Formula (VIII) comprising the steps of: reacting a compoundof Formula (II)

wherein R is hydrogen or (C₁-C₆)alkyl; X is Cl, Br, or I; and R¹ and Aare as defined in claim 1; with a boronic ester reagent to give acompound of Formula (X)

wherein R is hydrogen or (C₁-C₆)alkyl; and R¹ and A are as defined inclaim 1; and coupling the compound of Formula (X) with a compound ofFormula (IX)

wherein R², R³, R⁴, and Q are as defined in claim 1; in the presence ofa palladium catalyst, and optionally in the presence of a base, to givethe compound of Formula (VIII)

wherein R is hydrogen or (C₁-C₆)alkyl, R¹, R², R³, R⁴, A, and Q are asdefined in claim
 1. 35. The process of claim 34, wherein the boronicester reagent is pinnacol borane and the base is potassium carbonate.